Upload
others
View
4
Download
0
Embed Size (px)
Citation preview
3
4
Pharmacokinetics and Bioequivalence of Cefixime in Healthy Male and
Female Volunteers
By
Muhammad Mudassar Ashraf
B.Pharm., M.Phil.
A thesis submitted in partial fulfillment
of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
IN
PHARMACOLOGY
Institute of Pharmacy, Physiology & Pharmacology,
University of Agriculture, Faisalabad,
Pakistan.
2015
5
DECLARATION
I hereby declare that the contents of the thesis, “Pharmacokinetics and Bioequivalence of
Cefixime in Healthy Male and Female Volunteers” are product of my own research and no
part has been copied from any published source (except the references, standard mathematical or
genetic models/equations/formulae/protocols etc.). I further declare that this work has not been
submitted for award of any other diploma/degree. The university may take action if the
information provided is found inaccurate at any stage.
MUHAMMAD MUDASSAR ASHRAF
6
The Controller of Examinations,
University of Agriculture,
Faisalabad.
"We, the Supervisory Committee certify that the contents and form of thesis submitted by
Mr. Muhammad Mudassar Ashraf, 2010-ag-74, have been found satisfactory and recommend
that it be processed for evaluation by the External Examiner(s) for the award of degree".
Supervisory Committee:
CHAIRMAN: _________________________________
(Prof. Dr. IjazJavedHasan)
MEMBER: _________________________________
(Dr. Bilal Aslam)
MEMBER: _________________________________
(Prof. Dr. TanweerKhaliq)
7
To
The persons who
Encourage, help and support others,
Make a smile on the faces of others
and
Bring happiness and joys in other’s life
8
ACKNOWLEDGMENT
All thanks to Almighty Allah, The Compassionate and The Merciful, who knows whatever is
there in the Universe hidden or evident and who bestowed upon me the intellectual ability to
complete this research work successfully. Trembling lips and wet eyes praise for our beloved
Holy Prophet Muhammad (Sal-Allaho Alaihe Wasallam) for the internal and external blessings
for the literate, illiterate, rich, poor, weaker, stronger, able, disabled and deserted human beings.
I express my heartfelt gratitude to my learned Supervisor, Professor Dr. Ijaz Javed Hasan
for giving me the opportunity to undertake a doctorate research study under his guidance,
kindness, skillful suggestions, constructive criticism and encouragement throughout the course of
this study and his patience during the research and writing of this thesis. In-spite of his busy
schedule, he always acted as a real spiritual teacher and provided guidance and valuable
suggestions throughout my research efforts and write up of this manuscript. Under his kind
supervision this work was converted into a write up getting its present shape. Being his student is
the best step happened in my career. I am always amazed by his vision, energy, patience and
dedication to the research and his students. He trained me to grow as a scientist and as a person.
It took all his efforts to raise me as a professional scientist in pharmacology field.
I communicate my heartiest gratification to the respectable members of my Supervisory
Committee, Professor Dr. Tanveer Khaliq, Director, Institute of Pharmacy, Physiology and
Pharmacology, Faculty of Veterinary Science and Dr. Bilal Aslam for their guidance, incentive
teaching, positive criticism, expertise advice and very insightful, beneficial and constructive
suggestions during the course of my studies and to improve this research project. Also with deep
sense of honour, I say a bundle of thanks to Dr. Faqir Muhammad for their valuable suggestions
in completion of my Ph.D. coursework, seminar, synopsis defense, comprehensive exam and
present endeavor. I also appreciate the nice behavior of other faculty members including teaching
staff, clerical staff, lab attendants, office boys and sweepers.
Hearty appreciations are also due to my seniors (Dr. Haseeb, Dr. Tariq and all others),
juniors (Nasir, Majid Anwar, Batool Pirooz, Irum Nisar and all others) and all other well-wishers
specially Ahmad, Ahsan and Bilal Ashiq who never failed in helping me whenever their
assistance was needed. I take this opportunity to express my deep sense of gratitude to my old
respected teachers such as Dr. Naeem, Arshad, Shoukat, Asif Nadeem, Shoib Hakeem and Prof.
Dr. Saeed-ul-Hassan. I offer my sincere and cordial thanks for my friends Dr. Ehsan, Shafiq,
Usman and Zia who tried their best for arrangement of standard drug and HPLC facilities and
arrangements for me to execute this project. Many Prays and bundle of thanks to all the
volunteers (especially Mr. Saleem) who served themselves for my research project.
Last but not least, I also express my profound admiration to my precious family
members, especially to my father and mother, who have always believed in me, for their best
wishes and moral support during this whole period, with great patience even in presence of
9
severe financial crisis with a great load of responsibilities of my home and youngsters. I would
not be where I am today without their love and Prayers. It is with sincere gratitude to both of
them for their continuous interest, encouragement and inspiration. They always provided me an
atmosphere conductive to the pursuit to my academic goals, from my childhood up till now. I
attribute my sincere love and care to all my younger brothers and sisters who made possible the
accomplishment of this academic program with their maximum input and role in domestic life
management. I also love my uncle, Tariq Saleem, for his guidance throughout my professional
and higher educational period. I can never pay my all the blood relations, relatives and friends
for their Prays and well wishes for me.
At the end, my little angel, my baby doll, my cute daughter, Urwah Zainab whose great
smile, laugh, voice, weeping sound, body gestures, playing with little hands and legs, moving
and staring with attractive eyes and all her other styles always gave me a spirit and new
refreshment even when I was fully tired and fed up, during last few months of my research
phase. Finally I would like to extend my appreciation to my beloved, my life and my wife, Dr.
Umbreen for all her timeously encouragement and assistance as well as the support. I would not
have been able to face my challenges without her who enabled me to complete my Ph.D.
efficiently and proficiently. She always tried her best to stand with me during my entire crisis
and paid her full attention to me and my family with love and respect, whatever the condition is.
From whom I always expect to do all the best for my beloved relations more than I do or I can. I
would like to thank her also for her encouragement, tolerance and understanding, as weIl as, for
making me a proud "Daddy" during the course of this academic program. Whole remains
incomplete if I don’t discuss her and record my sincerest thanks to her with full of Praise and
Prays.
They all waited for a period of about five years with great patience in cool and soft way
for completion of my degree only for me and my career. I also completed my degree only for all
of them, with full attention and dedication. Whenever I lost my heart, it was only the thought of
all of them which gave me a new courage to carry on and move to my target. My existence is
with all of them and I am nothing without their love, kindness, encouragement and support. For
whom I want to earn only to the limit by which I can give them a prosperous life with fulfillment
of all basic needs. Again love you forever.
This thesis is acknowledged to the patience, long wait, sincerity, love, support, help,
encouragement, motivation, well wishes and Prays of all of them.
(Muhammad Mudassar Ashraf)
10
TABLE OF CONTENTS
CHAPTER NO. TITLE PAGE NO.
LIST OF FIGURES i
LIST OF TABLES iii
LIST OF APPENDICES Vii
ABSTRACT Viii
I INTRODUCTION 1
II REVIEW OF LITERATURE 3
III MATERIALS AND METHODS 116
IV RESULTS 129
V DISCUSSION 175
VI SUMMARY 188
REFERENCES 191
APPENDICES 233
11
LIST OF FIGURES
FIGURE NO. TITLE PAGE NO.
.12 Chemical structure of cefixime 31
.22 Chemical structure of cefixime tri-hydrate 32
1.a3 Chromatogram of blank plasma of healthy
volunteer 122
1.3b Chromatogram of 1 µg/ml of cefixime standard 122
1.c3 Chromatogram of 2 µg/ml of cefixime standard 123
1.d3 Chromatogram of 3 µg/ml of cefixime standard 123
1.e3 Chromatogram of 4 µg/ml of cefixime standard 124
1.f3 Chromatogram of 5 µg/ml of cefixime standard 124
2.3 Standard curve of cefixime 125
1.1.4
Mean ± SE plasma concentrations (µg/ml) of
cefspan on a semi logarithmic scale versus time
following a single oral administration 400 mg in 10
healthy adult female subjects
132
.24.1
Mean ± SE plasma concentrations (µg/ml) of
cefspan on a semi logarithmic scale versus time
following a single oral administration 400 mg in 10
healthy adult male subjects
134
3.1.4
Mean ± SE plasma concentrations (µg/ml) of
cefspan on a semi logarithmic scale versus time
following a single oral administration 400 mg in
136
12
healthy adult female and male subjects
4.1.4
Mean ± SE plasma concentrations (µg/ml) of
ceforal-3 on a semi logarithmic scale versus time
following a single oral administration 400 mg in 10
healthy adult female subjects
138
5.1.4
Mean ± SE plasma concentrations (µg/ml) of
ceforal-3 on a semi logarithmic scale versus time
following a single oral administration 400 mg in 10
healthy adult male subjects
140
6.1.4
Mean ± SE plasma concentrations (µg/ml) of
ceforal-3 on a semi logarithmic scale versus time
following a single oral administration 400 mg in
healthy adult female and male subjects
142
7.1.4
Mean ± SE plasma concentrations (µg/ml) of
cefspan and ceforal-3 on a semi logarithmic scale
versus time following a single oral administration
400 mg in healthy adult female subjects
144
8.1.4
Mean ± SE plasma concentrations (µg/ml) of
cefspan and ceforal-3 on a semi logarithmic scale
versus time following a single oral administration
400 mg in healthy adult male subjects
146
9.1.4
Mean ± SE plasma concentrations (µg/ml) of
cefspan and ceforal-3 on a semi logarithmic scale
versus time following a single oral administration
400 mg in healthy adult female and male subjects
148
13
LIST OF TABLES
TABLE NO. TITLE PAGE NO.
.12 Reported values of some pharmacokinetic
parameters of cephalosporins in human beings 6
.22 Different brands of cefixime available in Pakistan 40
.32 Reported values of some bioavailability parameters
of cephalosporins in human beings. 46
3.1
Description of 10 healthy adult female volunteers
involved during investigations of pharmacokinetics
and bioequivalence of cefixime
117
3.2
Description of 10 healthy adult male volunteers
involved during investigations of pharmacokinetics
and bioequivalence of cefixime
118
3.3 Chemicals Used for Analysis of cefixime by HPLC
Method 120
3.4 Definitions and/or formulae of kinetic parameters
derived 126
3.5 Definitions and/or formulae of bioavailability
parameters derived 127
4.1.1
Plasma concentrations (µg/ml) of cefspan following
a single oral administration 400 mg in 10 healthy
adult female subjects
131
4.1.2 Plasma concentrations (µg/ml) of cefspan following
a single oral administration 400 mg in 10 healthy
133
14
adult male subjects
4.1.3
Mean ± SE plasma concentrations (µg/ml) of cefspan
following a single oral administration 400 mg in
healthy adult female and male subjects
135
4.1.4
Plasma concentrations (µg/ml) of ceforal-3 following
a single oral administration 400 mg in 10 healthy
adult female subjects
137
4.1.5
Plasma concentrations (µg/ml) of ceforal-3 following
a single oral administration 400 mg in 10 healthy
adult male subjects
139
4.1.6
Mean ± SE plasma concentrations (µg/ml) of ceforal-
3 following a single oral administration 400 mg in
healthy adult female and male subjects
141
4.1.7
Mean ± SE plasma concentrations (µg/ml) of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female subjects
143
4.1.8
Mean ± SE plasma concentrations (µg/ml) of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult male subjects
145
4.1.9
Mean ± SE plasma concentrations (µg/ml) of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female and male subjects
147
4.2.1
Pharmacokinetic parameters of cefspan following a
single oral administration 400 mg in 10 healthy adult
female subjects
151
15
4.2.2
Pharmacokinetic parameters of cefspan following a
single oral administration 400 mg in 10 healthy adult
male subjects
152
4.2.3
Mean ± SE pharmacokinetic parameters of cefspan
following a single oral administration 400 mg in
healthy adult female and male subjects
153
4.2.4
Pharmacokinetic parameters of ceforal-3 following a
single oral administration 400 mg in 10 healthy adult
female subjects
154
4.2.5
Pharmacokinetic parameters of ceforal-3 following a
single oral administration 400 mg in 10 healthy adult
male subjects
155
4.2.6
Mean ± SE pharmacokinetic parameters of ceforal-3
following a single oral administration 400 mg in
healthy adult female and male subjects
156
4.2.7
Mean ± SE pharmacokinetic parameters of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female subjects
157
4.2.8
Mean ± SE pharmacokinetic parameters of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult male subjects
158
4.2.9
Mean ± SE pharmacokinetic parameters of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female and male subjects
159
4.3.1 Parameters for bioavailability of cefspan following a
single oral administration 400 mg in 10 adult healthy
163
16
female subjects
4.3.2
Parameters for bioavailability of cefspan following a
single oral administration 400 mg in 10 adult healthy
male subjects
164
4.3.3
Mean ± SE Parameters for bioavailability of cefspan
following a single oral administration 400 mg in
healthy adult female and male subjects
165
4.3.4
Parameters for bioavailability of ceforal-3 following
a single oral administration 400 mg in 10 adult
healthy female subjects
166
4.3.5
Parameters for bioavailability of ceforal-3 following
a single oral administration 400 mg in 10 adult
healthy male subjects
167
4.3.6
Mean ± SE Parameters for bioavailability of ceforal-
3 following a single oral administration 400 mg in
healthy adult female and male subjects
168
4.3.7
Mean ± SE parameters for bioavailability of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female subjects
169
4.3.8
Mean ± SE parameters for bioavailability of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult male subjects
170
4.3.9
Mean ± SE parameters for bioavailability of cefspan
and ceforal-3 following a single oral administration
400 mg in healthy adult female and male
171
17
4.4.1 Relative bioavailability for AUC and Cmax of ceforal-
3 and cefspan formulations in females 174
4.4.2 Relative bioavailability for AUC and Cmax of ceforal-
3 and cefspan formulations in males 174
LIST OF APPENDICES
APPENDICE
NO. TITLE PAGE NO.
1
Laboratory investigation of 10 healthy female
subjects involved in pharmacokinetic and
bioequivalence study of cefixime
233
2
Laboratory investigation of 10 healthy male
subjects involved in pharmacokinetic and
bioequivalence study of cefixime
253
18
ABSTRACT
In present study pharmacokinetics and bioequivalence of two brands of cefixime i.e.
Cefspan and Ceforal-3 were investigated in adult healthy female and male subjects. Plasma
concentration of Cefixime was determined by HPLC method. Pharmacokinetic parameters were
calculated following one compartment open model. The half life values were found 3.99±0.54 hr
and 3.12±0.39 hr in local adult female subjects and 5.01±0.361 hr and 4.72±0.72 hr in healthy
adult male subjects following administration of Cefspan and Ceforal-3, respectively. The values
of Vd in local adult female and male volunteers were 1.38±0.22 l/kg and 1.10±0.15 l/kg,
respectively, for Cefspan and 1.36±0.17 l/kg and 1.29±0.21 l/kg, respectively, for Ceforal-3. The
values of ClB for Cefspan and Ceforal-3 were 0.27±0.02 l/hr/kg and 0.31±0.02 l/hr/kg,
respectively, in local females and 0.16±0.02 l/hr/kg and 0.21±0.04 l/hr/kg, respectively, in local
males. The values of Cmax were found 2.24±0.23 μg/ml and 2.08±0.16 μg/ml in local adult
female subjects and 2.93±0.24 μg/ml and 2.53±0.31 μg/ml in healthy adult male subjects for
cefspan and ceforal-3, respectively. The values of Tmax were 4.05±0.35 hr and 4.11±0.16 hr for
cefspan and 3.87±0.32 hr and 3.95±0.26 hr for Ceforal-3 after oral administration in local adult
female and male volunteers, respectively. The values of AUC for Cefspan and Ceforal-3 were
27.12±2.25 μg.hr/ml and 23.99±1.07 μg.hr/ml, respectively, in local females and 36.58±3.10
μg.hr/ml and 32.99±5.01 μg.hr/ml, respectively, in local males. In indigenous male and female
human beings, pharmacokinetic and bioavailability parameters of cefixime showed different
values than those reported in literature reflecting environmental and genetic influence.
Pharmacokinetic and bioavailability parameters of cefixime also showed gender variation.
Moreover both brands of cefixime used in present study were found bioequivalent in either
gender.
19
CHAPTER I
INTRODUCTION
The differences of environmental conditions and genetic makeup of man and animals
between drug exporting countries and drug importing countries like Pakistan necessitate the
investigations of pharmacokinetic and bioavailability of drugs in local population as these
differences are manifested through the variation in pharmacokinetic and bioavailability
parameters suggesting different therapeutic dosage regimen to be employed clinically
(Muhammad, 1997; Javed et al., 2006; Javed et al., 2009 a,b; Hussain et al., 2014).
The primary goal of pharmacokinetic is to quantify rate and extent of drug absorption
(bioavailability), distribution and elimination in the intact, living animal or man; and to use this
information to predict the effect of alteration in the dose, dosage regimen, route of administration
and physiologic state on drug accumulation and disposition. Bioequivalence studies are
performed to assess whether two or more than two formulations of the same drug have the
relative rate and extent of absorption. The two brands of same drug can be considered
bioequivalent if their bioavailability i.e. rate and extent of absorption is same. All over the world,
it has become a serious issue that various formulations of the same drug show different
bioavailability therefore cannot be used alternatively. Bioequivalence studies highlight this
difference in the bioavailability and therapeutic efficacy, among formulations of same drug
owing impurities of active ingredients, different types of excepients, manufacturing faults as the
insufficiency of mixing procedure, coating protocol and granulation method (Esimone et al.,
2008; Maggio et al., 2008; Fujii et al., 2009). Further, lowering of health care costs may
tremendously increase the use of generic drug product. Market is flooded with national as well as
multinational drug products amongst which physicians must select therapeutic equivalents
(Miller and Storm, 1990; Foster, 1991). So, the need of bioavailability and bioequivalence
studies and clinical trials has been increased for local population, before marketing the drugs that
has been repeatedly emphasized by clinicians and health ministry (Vogel and Motulsky, 1986;
Haq, 1997).
20
Antibiotics play an important role in the treatment of various infectious diseases in men and
domestic animals. In treating microbial infection, it is essential that an effective concentration of an
antibacterial drug be rapidly attained at the focus of infection and maintained for an adequate time.
The concentration achieved varies with systemic availability of the drug based on its
physicochemical characteristics, dosage form, dosing rate, routes of administration and ability to
gain access to the infection site, subsequently influencing the bioavailability and pharmacokinetic of
the drug (Javed, 1998). Cefixime is a semi-synthetic, 3rd generation and orally acting
cephalosporin and it is well stable to inactivation by beta-lactamase enzymes (Baltimore, 2005).
It is effective against different human ailments including otitis media, gonorrhea, typhoid and
certain respiratory and urinary tract infections. Cefixime is a bactericidal drug causing its action
by inhibiting synthesis of the bacterial cell wall (Memon et al., 1997). Although, several studies
have been reported on the pharmacokinetics of cefixime (Evene et al., 2001; Ying et al., 2003;
Asiri et al., 2005; Zakeri et al., 2008), still the availability of literature on disposition kinetics
and bioavailability in local population of Pakistan especially with reference to gender variations
have been found to an limited extent.
Keeping in view the facts in preceding lines, present project was designed to investigate
pharmacokinetics and bioequivalence of two broadly used brands of cefixime in clinical
practices i.e. a multinational brand cefspan (Barrett Hodgson (Pvt.) Ltd. Karachi, Pakistan) and a
local brand ceforal-3 (Zafa Pharmaceuticals Laboratories (Pvt.) Ltd. Karachi, Pakistan) in
healthy adult female and male subjects. Thus the project encompassed a comparison of two
drugs in respect of brand dependent and gender dependant disposition kinetics and
bioavailability in female and male subjects.
21
CHAPTER II
REVIEW OF LITERATURE
2.1 Cephalosporins:
Cephalosporins are beta-lactam antibiotics derived in 1948 by Brotzu from the fungus
"Cephalosporium acremonium" from the sea near a sewer outlet on the Sardinian coast. Crude
filtrates from cultures of this fungus inhibited the growth or Staph. aureus In-vitro and cured
staphylococcal infections and also treated typhoid fever in man (Goodman and Gilman’s, 1996).
2.1.1 Mechanism of action of antibiotics:
Way the antibiotics act and produce their effects on the microbes have been categorized
mainly into four types; inhibition of synthesis of microbial cell wall, inhibition of bacterial cell
membrane synthesis, inhibition of the synthesis of nucleic acid and inhibition of protein
synthesis (Prescott and Baggot, 1988).
2.1.2 Mode of action of cephalosporin:
Cell wall of bacteria is important for supporting the underlying plasma membrane against
internal osmotic pressure and prevents penetration of antibacterial agents. It also prevents easy
access of lysozyme (an enzyme, which can destroy cell wall structures and is found in white
blood cells and tissue fluids) to the cell wall that contains peptidoglycan. About 30 bacterial
enzymes involves in the biosynthesis of peptidoglycan. The last step of peptidoglycan synthesis
is transpeptidation reaction, which is inhibited by beta-lactam antibiotics, results in inhibition of
bacterial cell wall synthesis (Tomasz, 1986).
Cephalosporins attach to the bacterial cell wall through penicillin-binding proteins
(PBPs). These proteins are under chromosomal control; therefore mutation may alter their
number and affinities for specific beta-lactam drugs (Neu, 1988). In addition cephalosporins
probably also participates in removal or inactivation of an inhibitor of autolytic enzymes
(hydrolysis) of bacterial cell walls. The activation of these autolytic enzymes results in the lyses
of cell wall and ultimately bacterial death (Tomasz, 1986).
22
2.1.2.1 Penicillin binding proteins:
Penicillin Binding Proteins (PBPs)
An important step, transpeptidase reaction, in bacterial cell wall synthesis is catalyzed by
Penicillin-binding Proteins (PBPs). In this step a terminal alanine is removed in a cross
linking reaction with a nearby peptide.
Antibacterial action of cephalosporin occurs through binding to these proteins and
resulting in inhibition of activity of these proteins.
Resistance to ß-lactams is developed in bacteria due to alteration of PBPs (penicillin-
binding proteins) [Chambers et al., 1998].
2.1.2.2 Development of antibiotic resistance:
Resistance may be acquired to beta-lactam antibiotics either by developing new PBP
genes or by mutation within existing genes of PBPs (e.g. staphylococcal resistance to
methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and
meningococcal resistance) [Chambers et al., 1998].
Resistance to ß-lactams:
There are several mechanisms of development of bacterial resistance to ß-Lactams and
elaboration of the enzyme ß-lactamase is most important among these. This enzyme
hydrolyzes the ß-lactam ring. Genes for ß-lactamase may be present in both bacteria
(Gram-positive and Gram-negative). Some inhibitors for this enzyme such as sulbactum
and clavulanic acid can minimize this resistance by binding to some ß-lactamases.
Alteration of PBPs is a second mechanism for bacterial resistance development.It may
occur either by mutation of the existing genes or by acquiring new genes or pieces of
genes, as described earlier.
A 3rd mechanism which is seen in Gram -ve bacteria is due to alteration of genes
specifying the porins (outer membrane proteins) and thus reducing the permeability of β -
lactams (e.g. resistance of Enterbacteriaceaeto some cephalosporins and that of
Pseudomonas spp. to ureidopenicillins).
Same bacterial cells may show multiple resistance mechanisms (Archer and Polk, 1998).
23
2.1.3 Classification and antibacterial spectrum of cephalosporin:
Cephalosporin may be classified by their spectrum of antimicrobial activity into four
generations namely first, second, third and fourth generation (Karchmer, 1995). Third-generation
cephalosporin drugs (such as ceftriaxone and cefixime) possess broader spectrum of activity
against the Gram-negative bacilli than agents of 1st or 2nd generation, but are less effective
against Gram +ve cocci as compare to earlier generation drugs. However, these are active against
beta-lactamase producingNeisseria species and H. influenza (Donowitz and Mandell, 1988).
2.1.4 Pharmacokinetics of cephalosporin:
Pharmacokientic parameters of cephalosporins in human being and in animals have been
presented in Table 2.1.
2.1.4.1 Absorption:
Some cephalosporin such as cefixime, cefadroxil, cepharadine, cephalexin and cefaclor
are well absorbed from the intestinal tract. Therefore, they can be given orally. Other
cephalosporins such as ceftriaxone is poorly absorbed through the intestinal tract, thus it is
administered parenterally.
2.1.4.2 Distribution:
Cephalosporins distribute widely throughout the body. They can easily penetrate into
pleural, pericardial, CSF, placenta and joint fluids. In addition, cephalosporins reach high
concentration in skin, muscles, stomach wall, liver, spleen and kidney. The Vd of cephalosporins
ranges born 0.l to 0.4 L and their degree of plasma protein binding ranges from 17% to 90%.
Cephalosporins are not extensively bio-transformed, but are distributed and excreted in active
form.
2.1.4.3 Excretion:
Cephalosporins are mainly eliminated via the kidney. However, about 20% of a given
dose of cefixime is excreted via urine in unchanged form while remainder (80%) is excreted
throughbile (Klepser et al., 1995).
24
Table 2.1: Reported values of some pharmacokinetic parameters of cephalosporins in human beings.
Cephalosporin Subjects
Dose
Route
Pharmacokinetic parameters
Reference
mg
mg
per
kg
B β 1/2t dV BCl
µg/ml hr-1 hr L/kg L/hr/kg
Cephalexin Cats - 10
IV
- 0.42 1.68 0.33 0.02
Albarellos et al.,
2011
Cefepime
Cystic
fibrosis
patients - - - - - - 0.32 -
Ambrose et al.,
2002
Cefepime
Patients with
LRTIs - - - - - - 0.22 -
Ambrose et al.,
2002
Cefepime Sepsis - - - - - - 0.47 -
Ambrose et al.,
2002
Cefepime Young - - - - - - 0.21 -
Ambrose et al.,
2002
Cefepime Elders - - - - - - 0.23 -
Ambrose et al.,
2002
Cefixime
Healthy
male
200
mg/10ml - Oral - - 2.23 - -
Asiri et al.,
2005
25
Cefixime -
200
mg/10ml -
Oral - - 3.32 - -
Asiri et al.,
2005
Cefixime - 200 - Oral Tablet - - 3 - - Baltimore, 2005
Cefixime Young
400 mg
OD for 5
days - - - - 3.5 - - Baltimore, 2005
Cefixime Elderly
400 mg
OD for 5
days - - - - 4.2 - - Baltimore, 2005
Cefepime - 500 -
IV
- - 1.9 - -
Barbhaiya et al.,
1990c
Cefepime
Human
subjects 250 -
IV
- - 1.8 - -
Barbhaiya et al.,
1990c
Cefepime - 1000 -
IV
- - 1.9 - -
Barbhaiya et al.,
1990c
Cefprozil
Beagle dogs 125
IV
- - 80 - -
Barbhayia et al.,
1992a
Cefprozil
Beagle dogs 125 Oral - - 104 - -
Barbhayia et al.,
1992a
Cefepime
Young
males 1000
IV
- - 2.26 0.21 0.0924
Barbhaiya et al.,
1992b
Cefepime Young - - IV - - 2.15 0.21 0.0936 Barbhaiya et al.,
26
females 1992b
Cefepime
Elderly
males - -
IV
- - 3.05 0.23 0.0666
Barbhaiya et al.,
1992b
Cefepime
Elder
Females - -
IV
- - 2.92 0.24 0.0732
Barbhaiya et al.,
1992b
Cefaclor Fasting 250 - Oral - - 1.17 - -
Barbhayia et al.,
1990
Cefaclor Fasting 250 - Oral - - 1.16 - -
Barbhayia et al.,
1990
Cefprozil With food 250 - Oral - - 0.83 - -
Barbhayia et al.,
1990
Cefprozil With food 250 - Oral - - 0.86 - -
Barbhayia et al.,
1990
Cefprozil
Healthy
male
volunteers 250 Oral - - 1.4 - -
Barbhayia et al.,
1990a
Cefaclor
Healthy
male
volunteers 250 - Oral - - 0.5 - -
Barbhayia et al.,
1990a
Cefprozil
Healthy
male
volunteers 500 - Oral - - 1.3 - -
Barbhayia et al.,
1990a
27
Cefaclor
Healthy
male
volunteers 500 - Oral - - 0.6 - -
Barbhayia et al.,
1990a
Cefprozil Humen 250 Oral - - 1.28 - -
Barbhayia et al.,
1990b
Cefprozil
- 500 Oral - - 1.29 - -
Barbhayia et al.,
1990b
Cefprozil
- 1000 Oral - - 1.27 - -
Barbhayia et al.,
1990b
Cefotetan - - - - - - 4.4 - - Bergan, 1987
Cefonicid - - - - - - 5 - - Bergan, 1987
Cefpiramide - - - - - - 3.5 - - Bergan, 1987
Ceftriaxone - - - - - - 8.5 - - Bergan, 1987
Cefixime Dogs - 6.25
IV
- - 6.4 2.2 0.24
Bialer et al.,
1987
Cefixime Dogs - 25
IV
- - 6.4 2.8 0.312
Bialer et al.,
1987
Cefpodoxime
Healthy
adult 100-400 Oral - -
1.9-
2.8 - - Borin, 1991
Cefoperazone Neonates - 50 - - - 5.5 0.12 0.6
Bosso et al.,
1983
Ceftriaxone Healthy 2000 IV - - 6.2 11.7 1.30 Bourget et al.,
28
volunteers 1993
Ceftriaxone
Pregnant
women 2000 Infusion - - 6.77 12.54 1.28
Bourget et al.,
1993
Cefixime
Normal
subjects 50 - - - - 3 0.1 0.4
Brittain et al.,
1985
Cefixime - 100 - - - - 3 0.1 0.4
Brittain et al.,
1985
Cefixime - 200 - - - - 3 0.1 0.4
Brittain et al.,
1985
Cefixime - 400 - - - - 3 0.1 0.4
Brittain et al.,
1985
Cefixime
Healthy
subjects 200 - - - - 3 - -
Brogden and
Campoli-
Richards, 1989
Cefepime Neonates - 50 - - - 4.9 0.43 1.1
Capparelli et al.,
2005
Cefoperazone Calves - - - - - 0.9 - -
Carli et al.,
1986
Cefoperazone
In women
after
postpartum 1000
IV
- - 1.35 10.51 5.38
Charles and
Bryan, 1986
Cefotaxime 1000 IV - - 1.32 58.17 31.2 Charles and
29
Bryan, 1986
Cefpodoxime
Healthy
adult 400 - Oral - - 3.5 - 5.40
Chugh and
Agrawal, 2003
Ceftazidime
Male
without
mechanical
ventilation - - - - - 1.81 22.8 7.2
Connil et al.,
2007
Ceftazidime
Female
without
mechanical
ventilation - - - - - 1.98 28.1 6.6
Connil et al.,
2007
Ceftazidime
Male with
mechanical
ventilation - - - - - 2.15 31.6 6.1
Connil et al.,
2007
Ceftazidime
Female with
mechanical
ventilation - - - - - 2.17 49.4 5.7
Connil et al.,
2007
Ceftolozane
Neutropenic
mice 25 - - - 11.6 - -
Craig and
Andes, 2007
Ceftolozane - 100 - - - 13.8 - -
Craig and
Andes, 2007
Ceftolozane - 400 - - - 14.1 - - Craig and
30
Andes, 2007
Cefoperazone
Healthy
male and
female adult 2000 -
IV
- - 10.3 1.1 1.782
Deeter et al.,
1990
Cefotaxime
- 2000 -
IV
- - 20 10.2 10.34
Deeter et al.,
1990
Ceftriaxone
- 2000 -
IV
- - 15.2 6.2 6.48
Deeter et al.,
1990
Ceftazidine
- 2000 -
IV
- - 3.7 9.4 4.76
Deeter et al.,
1990
Ceftizoxime
- 2000 -
IV
- - 3.5 7.9 3.75
Deeter et al.,
1990
Cefazolin Neonates - 30 - - - - 0.28 0.8
Deguchi et al.,
1988
Cefixime
Normal
subjects 200 - Oral - - 3.73 - 11.64
Dhib et al.,
1991
Cefixime
Uremic
patients 200 - Oral - -
12 to
14 - -
Dhib et al.,
1991
Ceftazidime
Healthy
adult 2000 - - - - 1.75 0.21 6.4
Drusano et al.,
1984
Cefixime - 200 - Oral - - 3.4 17 3.55
Duverene et al.,
1992
31
Cefixime - 200 -
IV
- - 3.3 17 -
Duverene et al.,
1992
Cefixime Sheep - - - - - - 4.67 62.48
Eldalo et al.,
2004
Cefazolin
In
parturients
undergoing
cesarean
surgery 2000 - - - 0.34 - 9.44 7.18
Elkomy et al.,
2014
Cefixime
Healthy
male
subjects - - - - -
3.0to4
.0 - -
Faulkner et al.,
1987
Cefixime
Healthy
volunteers 200 -
Solution
IV - -
3.5
3.2to - -
Faulkner et al.,
1988
Cefixime
Healthy
volunteers 200 -
Oral
solution - -
3.5
3.2to - -
Faulkner et al.,
1988
Cefixime
Healthy
volunteers 200 -
Oral
capsule - -
3.5
3.2to - -
Faulkner et al.,
1988
Cefixime
Healthy
volunteers 400 -
Oral
capsule - -
3.5
3.2to - -
Faulkner et al.,
1988
Cephalexin Calves - - - - - 2 0.3 1.9
Garg et al.,
1992
32
Ceftriaxone
Calves
(buffalo) - 10
IV
- - 1.3 0.5 0.264
Gohil et al.,
2009
Ceftriaxone
Calves
(buffalo) - 10 IM - - 4.4 1.5 0.24
Gohil et al.,
2009
Cefoperazone
Parturients
in immediate
postpartum
period after
cesarean
section 2000 -
IV
- - 2.53 0.18 0.066
Gonik et al.,
1986
Ceftazidime
Female
dromedary
camels -
10
IV
- - 2.85 - -
Goudah and
Sherifa, 2013
Ceftazidime - -
10
IM - - 3.2 - -
Goudah and
Sherifa, 2013
Cefepime
Healthy
rabbits - - IM - - 3.85 - -
Goudah et al.,
2006
Cefepime
Febrile
rabbits - - IM - - 3.01 - -
Goudah et al.,
2006
Cefotaxime Neonates - 25 - - - 3.7 0.43 1.57
Gouyon et al.,
1990
Cefixime Healthy 400 - Oral - - 3.2 1.1 8.46 Guay et al.,
33
subjects 1986
Ceftriaxone Sheep - - - - - - 0.3 3.7
Guerrini et al.,
1985
Cefoperazone Sheep - 47
IV
- - - 0.2 2.7
Guerrini et al.,
1985
Cefoperazone
Cross bred
calves - 4
IV
5.44 - 2.05 1.11 -
Gupta et al.,
2007
Cefoperazone
Cross bred
calves - 20 IM 5.28
0.30
1 2.31 2.95 1.28
Gupta et al.,
2008
Cefixime
Pregnant and
lactating rats - 17.8
IV
Infusion - - 6.9 - -
Halperinwalega
et al., 1988
Cefixime
Healthy
adult male 400 Oral - - 2.6 - 27
Healy et al.,
1989
Cefuroxime
Malnourishe
d rats
-
2.2 Oral - - 37 - -
Hernandez et
al., 2008
Cefuroxime
Controlled
rats
-
2.2 Oral - - 37.6 - -
Hernandez et
al., 2008
Cefepime
Febrile
buffalo
calves - 10
IV
19.6
0.23
4 3 0.48 0.0988
Joshi and
Suresh, 2009
Cephalexin
Healthy
adult 1000 - Oral - -
0.5-
1.2 ˂3 -
Kalman and
Steven, 1990
34
Cefadroxil
Healthy
adult - - Oral - -
1.1-
2.0 - -
Kalman and
Steven, 1990
Cephradine
Healthy
adult 1000 - Oral - -
0.7-
2.0
9.65-
15.4 -
Kalman and
Steven, 1990
Cephalothin
Healthy
adult 1000 -
Parenteral-
IV - -
0.5-
1.0
5.0-
14.0 -
Kalman and
Steven, 1990
Cephapirin
Healthy
adult 1000 -
Parenteral-
IV - -
0.3-
0.5 8.8 -
Kalman and
Steven, 1990
Cefazolin
Healthy
adult 1000 - Parenteral - -
1.2-
2.2 7.0-9.0 -
Kalman and
Steven, 1990
Cefuroxime
Healthy
adult 1000 - Oral - -
1.0-
2.0 - -
Kalman and
Steven, 1990
Cefuroxime
Healthy
adult 1000 - Parenteral - -
1.0-
2.0 - -
Kalman and
Steven, 1990
Cefamandole
Healthy
adult 1000 - Parenteral - -
0.5-
2.1 - -
Kalman and
Steven, 1990
Cefoxitin
Healthy
adult 1000 - Parenteral - -
0.7-
1.1 - -
Kalman and
Steven, 1990
Cefmetazole
Healthy
adult 1000 - Parenteral - - 1 - -
Kalman and
Steven, 1990
Cefotetan
Healthy
adult 1000 - Parenteral - -
2.8-
4.6 - -
Kalman and
Steven, 1990
35
Cefaclor
Healthy
adult - - Oral - -
0.5-
1.0 - -
Kalman and
Steven, 1990
Cefdinir
Healthy
adult 300 - Oral - -
1.5-
2.0 - -
Kalman and
Steven, 1990
Cefoperazone
Healthy
adult 1000 -
IV
- -
1.6-
2.6 - 15-30
Kalman and
Steven, 1990
Cefotaxime
Healthy
adult 1000 -
IV
- -
0.9-
1.7 - -
Kalman and
Steven, 1990
Ceftizoxime
Healthy
adult 1000 -
IV
- -
1.4-
1.9 - 28-31
Kalman and
Steven, 1990
Ceftriaxone
Healthy
adult 1000 -
IV
- -
5.4-
10.9 - -
Kalman and
Steven, 1990
Ceftazidime
Healthy
adult - - Parenteral - -
1.4-
2.0 - 80-90
Kalman and
Steven, 1990
Cefixime
Healthy
adult 400 - Oral - -
3.0-
4.0 - 18
Kalman and
Steven, 1990
Cefroxadine
Healthy
adult - - - - - 1 - -
Kang et al.,
2006
Cefadroxil
Healthy
adult 500 - - - - 1.5 - 1.8
Kano et al.,
2008
Cefuroxime
Healthy
volunteers 500 - Oral - - 1.29 - -
Kaza et al.,
2012
36
Cefuroxime
Healthy
volunteers 500 - Oral - - 1.28 - -
Kaza et al.,
2012
Cefixime
Healthy
male and
female
volunteers 200 - Oral Tablet - - 2.91 - -
Kees et al.,
1990
Cefixime - 200 - Oral syrup - - 3.13 - -
Kees et al.,
1990
Cefixime - 200 -
Oral
suspension - - 3.01 - -
Kees et al.,
1990
Cefixime
Healthy
volunteers 200 - Oral Tablet - -
2.9-
3.1 - -
Kees et al.,
1990 and Kees
and Naber, 1990
Cefixime - 200 - Oral syrup - -
2.9-
3.1 - -
Kees et al.,
1990 and Kees
and Naber, 1990
Cefixime - 200 -
Oral
suspension - -
2.9-
3.1 - -
Kees et al.,
1990 and Kees
and Naber, 1990
Cefixime
Healthy
male 200 - Oral Tablet - - 4.98 - -
Lan-Ying et al.,
2004
Cefixime - 200 - Oral - - 5.28 - - Lan-Ying et al.,
37
Capsule 2004
Cefixime - - - - - - 3 - -
Legget et al.,
1990
Cefaclor
Female
subjects 500
Oral
withwater - - 0.59 - - Li et al., 2009
Cefaclor
Female
subjects 500
Oral
withjuice - - 0.62 - - Li et al., 2009
Cefpodoxime - 400 - Oral - - 2.6 - - Liu et al., 2005
Cefixime - 400 - Oral - - 4 - - Liu et al., 2005
Cefixime Chinese men 400 - - - - 4.2 - - Liu et al., 2007
Ceftobiprote
500 -
IV
- 5.18 - 7.65 0.51
Lodise et al.,
2007
Cefixime - - - - - - 3 - - Low, 1995
Cefixime
Renal
patients 100 - - - - 4.2 - -
Maeda et al.,
1986
Ceftriaxone
Calves
(cow) - 10
IV
- - 1.6 0.4 3.2
Maradiya et al.,
2010
Ceftriaxone
Calves
(cow) - 10 IM - - 5 1.2 2.7
Maradiya et al.,
2010
Ceftriaxone
Cardiac
patients 1000 -
IV
- - 8.1 18.3 23.2
Martin et al.,
1996
Cefepime Mice - 80 - - - 0.38 - 16.7 Mathe et al.,
38
2006
Ceftriaxone
Healthy
adult 1000 - IM - -
5.0-
9.0 - -
Meyers et al.,
1983
Ceftolozane
Females and
males 500 - - - - 2.48 11.8 5.18
Miller et al.,
2012
Cefixime - 200 - Oral - - 3.15 - -
Min-Ji et al.,
2004
Cefixime - 200 - Oral - - 3.31 - -
Min-Ji et al.,
2004
Cephalexin
Healthy
male and
female
volunteers 500 - - - - 1.06 25.13 13.21
Mircioiu et al.,
2007
Cephalexin
Healthy
volunteers 500 - - - 0.72 0.98 21.68 15.34
Mohamed et al.,
2011
Cephalexin
Healthy
volunteers 500 - - - 0.73 0.99 20.96 14.81
Mohamed et al.,
2011
Cephalexin
Healthy
volunteers 500 - - - 0.73 0.98 24.64 17.81
Mohamed et al.,
2011
Cefixime
Healthy
male
volunteers 200 - Oral - - 3.3 - -
Montay et al.,
1989
39
Cefixime
Healthy
male
volunteers 400 - Oral - - 3.7 - -
Montay et al.,
1991
Cefixime
Patients
undergoing
cholecystect
omy
2200 x
mg/day
- - - - 3 - -
Moorthi et al.,
1990
Cefixime Children - 1.5 - - - 2.7 - -
Motohiro et al.,
1986
Cefixime Children - 3 - - - 2.8 - -
Motohiro et al.,
1986
Cefixime - 50 -
Oral
granules - - 3.09 - -
Motohiro et al.,
1986
Cefixime - 50 -
Oral
capsule - - 2.87 - -
Motohiro et al.,
1986
Ceftriaxone Neonates - 50 - - - 15.4 0.33 0.28
Mulhall et al.,
1985
Cefixime
Healthy
volunteers 50 mg bid - - - - 2.5 - -
Nakashima et
al., 1987
Cefixime
Healthy
volunteers
100 mg
bid - - - - 2.4 - -
Nakashima et
al., 1987
Cefixime Healthy 200 mg - - - 2.3 - - Nakashima et
40
volunteers bid al., 1987
Cefixime - 200 - - - - 2.5 - - Nies, 1989
Ceftriaxone Humen
Water
asdiluent - IM - 0.1 7.1 9.37 0.904
Patel et al.,
1982
Ceftriaxone -
Lidocain
asdiluent - IM - 0.1 7 9.22 0.890
Patel et al.,
1982
Ceftriaxone
Young
subjects 1000 -
IV
-
0.09
3 7.5 11 -
Patel et al.,
1984
Ceftriaxone
Adult
subjects 1000 -
IV
-
0.07
8 8.9 10.7 -
Patel et al.,
1984
Cefepime Calves - 5
IV
- - 3.7 0.43 1.81
Patel et al.,
2006
Cefepime
Cow
(calves) - 5
IV
- - 3.7 0.6 1.8
Patel et al.,
2006
Cefepime
Cow
(calves) - 5 IM - - 6.7 1 1.7
Patel et al.,
2006
Cefepime Sheep - 20
IV
- - 2.5 0.4 2.5
Patel et al.,
2010
Cefepime Sheep - 20 IM - - 5.2 1.1 0.2
Patel et al.,
2010
Cefepime Goat - 10
IV
- - 2.7 0.5 2.2
Patni et al.,
2008
41
Cefepime Goat - 10 IM - - 4.9 - 1.3
Patni et al.,
2008
Cefpodoxime
Male /
female sub
jects 200 - Oral -
0.12
4 5.9 - -
Peter et al.,
1992
Ceftriaxone
Males and
females 2000 -
IV
- - 7.5 11.7 1.284
Pletz et al.,
2004
Cephapirin
Cow
(lactating) - - - - - - - 13
Prades et al.,
1988
Cefpirome
Buffalo
calves - 10 IM 9.23 0.29 2.39 0.42 0.12
Rajput et al.,
2007
Cefpirome
Crossbred
calves - 10 IM 12 0.34 - - -
Rajput et al.,
2012
Ceftizoxime Neonates - 5-25 - - - 7.2 0.37 0.68
Reed et al.,
1991
Cefoxitin Neonates - 30 - - - 1.43 0.5 4.5
Regazzi et al.,
1983
Cefuroxime Neonates - 10 - - - 4.6 - -
Renlund and
Pettay, 1977
Ceftriaxone
Male and
female
adults 250 -
IV
- - 8.16 - -
Robert et al.,
2001
42
Ceftriaxone - 250 - IM - - 7.6 - -
Robert et al.,
2001
Cefixime - 400 -
Oral
- - 3.61 - -
Robert et al.,
2001
Ceftazidime Sheep - - - - - 1.6 0.4 - Rule et al., 1991
(Bioximet)
Cefuroxime
Healthy
volunteers 500 - Oral -
0.61
3 1.169 - -
Sabati et al.,
2014
(Zinnat)
Cefuroxime
Healthy
volunteers 500 - Oral -
0.63
2 1.142 - -
Sabati et al.,
2014
Cefixime - - - - - - 3 - - Saito, 1985
Cefotaxime
Bufalo
calves - 13 - 5.76 0.54 1.31 1.34 713.6
Sharma and
Anil, 2003
Cefotaxime
Bufalo
calves - 10
SC
6.33
0.39
2 1.77 1.17 0.45
Sharma and
Anil., 2006
Ceftazidime
Febrile
buffalo
calves - 10
IV
31.04 0.19 3.73 0.2 47.9
Sharma and
Shah, 2012
Cefotaxime
Febrile
buffalo
calves - 10
IV
1.84
0.38
1 1.85 1.7 644
Sharma et al.,
2006
Cephradine
Healthy
adult male 250 - PO
2.79
mg/ml 1.74 0.44 9.65 15.4
Shoaib et al.,
2008
43
Cefixime
Healthy
volunteers 200 - Oral Tablet - - 2.9 - -
Shu-Ying et al.,
2009
Cefixime - 200 -
Oral
capsule - - 2.7 - -
Shu-Ying et al.,
2009
(Cis-isomer)
Cefprozil
Lactating
females - - - - 1.69 - 0.164
Shyu et al.,
1992
(Trans-isomer)
Cefprozil - - - - - - 1.35 - 0.161
Shyu et al.,
1992
Cefazolin Calves - - - - - 0.6 0.2 5.8
Soback et al.,
1987
Cefoxitin Calves - - - - - 1.1 - - Soback, 1988
Ceftazidime Male 1000 -
IV
- - 1.58 13.33 6.99
Sommers et al.,
1983
Ceftazidime Female 1000 -
IV
- - 1.5 11.05 5.82
Sommers et al.,
1983
Ceftazidime
Male 1000 - IM - - 1.83 22.09 28.9
Sommers et al.,
1983
Ceftazidime Female 1000 - IM - - 1.89 16.17 37.2
Sommers et al.,
1983
Cefoperazone
Healthy
Adult 1000 -
IV
- - 2.6 - -
Sootornpas et
al., 2011
Ceftazidime Juvenile - 20 IV - 0.03 20.6 - - Stamper et al.,
44
loggerhead
sea turtles
1999
Ceftazidime
- -
20
IM - 0.04 19.1 - -
Stamper et al.,
1999
Cefoperazone
Healthy
Adult - - - - - 1.87 0.14 4.04
Standiford et al.,
1982
Cefotaxime
Healthy
Adult - - - - - 1.18 0.23 14.04
Standiford et al.,
1982
Cefixime
Healthy
male
volunteers 400 - - - - 3.8 - -
Stone et al.,
1988
Ceftriaxone Sheep - 10
IV
- - 1.2 0.4 3.9
Swati et al.,
2010
Ceftriaxone Sheep - 10 IM - - 2.2 0.4 2.2
Swati et al.,
2010
Ceftifur Healthy pigs - -
IV
- - 21 0.527 0.017
Tantituvanont et
al., 2009
Ceftriaxone Goat - 20
IV
- - 1.5 0.6 4.5
Tiwari et al.,
2009
Ceftriaxone Goat - 20 IM - - 2 0.5 3
Tiwari et al.,
2009
Ceftriaxone Transplant 2000 - IV - 0.05 13.1 - - Toth et al., 1991
45
recepients 3
Ceftriaxone
Normal
subjects 2000 -
IV
- - 5.8 - - Toth et al., 1991
Ceftizoxime
Female
andmale
subjects 2000 -
IV
- - 2.04 0.34 0.166
Valle and Marc,
1991
Cefotaxime - 2000 -
IV
- - 1.43 0.28 0.229
Valle and Marc,
1991
Ceftazidime Neonates - 25 - - - 8.15 0.32 0.46
VandenAnker et
al., 1995
Cefixime
Patients of
T-tube
drainage - - - - - 3.5 - 11.7
Westphal et al.,
1992
Cefixime
Patients with
RTIs (M&F) 200 - - - 0.22 3.09 0.15 0.0324 Yi et al., 1995
Cefuroxime
sodium
Beagle
Dogs - 40
IV
- - 1.21 0.61 0.34
Zhao et al.,
2012
Cefuroxime
lysine - - -
IV
- - 0.91 0.42 0.31
Zhao et al.,
2012
Ceftriaxone
Males and
females 1000 - IM - - 8.2 - -
Zhou et al.,
1985
Ceftriaxone - 1000 - IV - - 8.1 8.5 - Zhou et al.,
46
1985
Cefixime - - -
Oral and
IV - -
3.5to4
.0 0.3 - Ziv et al., 1995
LRTIs = Lower Respiratory Tract Infections PO = Per Oral OD = Once Daily
IV = Intra Venous IM = Intra Muscular SC = Sub Cutaneous
47
2.1.5 Route of administration of cephalosporin and dosage regimens:
β-lactams have time-dependent killing activity against infectious organisms. To achieve
their optimal effect the concentration of drug in serum must be above minimum inhibitory
concentration. Therefore, dosing frequency at right time is essential (Walker et al., 2012).
Cephalosporins may be given orally, intramuscularly and intravenously depending on the
specific agent and therapeutic indications. The daily oral dose of cephalosporins ranges from 5 to
50 mg/Kg and this amount is usually divided into 2-4 equal doses. The parenteral dose is 50-200
mg/Kg and this amount is also divided into 2-6 equal doses depending on the half-life of
individual drugs.
2.1.6 Therapeutic uses of cephalosporin:
It was reported that cephalosporins are effective as therapeutic as well as prophylactic
drugs. Thus, these are considered the drug of choice for the serious infections caused by
Entrobacter, Klebsiella, Serratia, Hemophillus species and Proteus providencia. Ceftriaxone and
cefixime are the drugs of choice now to treat typhoid and meningitis in children and adults
(Donowtiz and Mandell 1988).
2.1.7 Adverse reactions of cephalosporin:
Hypersensitivity reactions including rash, fever, eosinophlia, serum sickness and
anaphylaxis are the most common side effects of cephalosporins (Petz, 1978). It was found that
the incidence of allergic reactions to the cephalosporins increased in penicillin sensitive patients
and it may due to their similar structures (Bennett et al., 1983) and enhanced nephrotoxicity of
aminoglycoside antibiotics by cephalosporins was also reported (Barza, 1978).
Prothrombin activity may be reduced by cephalosporins. Those who are at risk include
the patients of liver or kidney dysfunctions, patients who previously have been stabilized on
anticoagulants, as well as the patients who have received the protracted course of antibacterial
drugs and persons having poor nutritional state. Patients at risk should be monitored for
prothrombin time and as an indication exogenous vitamin K should be administered (Baltimore,
2005).
48
2.1.8 Cephalosporin in typhoid:
Treatment of Typhoid treatment with the existing popular antibiotic drugs in the recent
years has not been satisfactory and this may be due to that the strain of Salmonella typhi has got
emergent resistance all over the world including Pakistan. Ceftriaxone, cefixime and other third
generation cephalosporins have emerged as good and satisfactory alternatives to previous oral
drugs used for typhoid fever. Previous studies in children with MDR typhoid fever have shown
more than 90% successful cure rate with parenteral ceftriaxone in Pakistan (Naqvi et al., 1992).
Typhoid fever is a complicated, severe and prolonged disease produced by Salmonella
typhi (Gram-negative bacilli) through contaminated food or water intake. Typhoid fever has
incubation period of usually 10- 14 days but may vary from 7-21 days depending on the number
of ingested organisms (Homick et al., 1970).
Recently, the incidence of typhoid fever infection has increased considerably and there
are more than five million cases of typhoid fever worldwide yearly reported by the World Health
Organization (Edelman and Levin, 1986). Typhoid fever is a major cause of mortality and
morbidity in developing countries (Taylor et al., 1983) including Pakistan (Rathore et al., 1996;
Abdulbaqi and Rab, 1996).
For treating the typhoid fever, a large number of antibiotics are used such as ampicillin,
chloramphenicol and trimethoprim-sulphamethoxazole. These drugs have been the therapy of
choice for enteric fever. A marked increase in resistant strains of Salmonella typhi have been
reported showing resistance to ampicillin, chloramphenicol and trimethoprim-sulphamethoxazole
around the world (Rowe et al., 1990) including Pakistan (Bhutta et al., 1994; Rathore et al.,
1996). The ineffectiveness of these drugs in treatment of typhoid fever is not fully understood
but it may be due to insufficient penetration of the drug into the infected cell or poor anti-
bactericidal action of antibiotics (Abdulbaqi and Rab 1996).
Outbreak of multidrug-resistant (MDR) Salmonella typhi is a major problem related to
public health. The first serious problem of MDR Salmonella typhi to chloramphenicol was
reported in Mexico in 1972. Thereafter, the MDR Salmonella typhi strains resistant to
chloramphenicol were reported in Vietnam (Butler et al., 1993), Bangladesh (Samadi, 1982),
India (Chandra et al., 1984) and Pakistan (Rathore et al., 1996). Although oral quinolones offer
49
an effective and safe drug alternative for treatment of MDR typhoid fever in adults (Bryan et al.,
1986), there are still major concerns in children about its adverse effects (Lumbiganon et al.,
1991; Navolekar et al., 1992). Thus, new inexpensive effective antibiotics with less duration of
therapy are needed because of alarming spread of resistant strains of the Salmonella typhi
throughout the world.
Recently, third generation cephalosporins have proved a satisfactory substitutes to
previous oral therapies for typhoid fever. Response to these drugs can be changed by many
factors including age and complications occurring simultaneously with typhoid fever (fever,
illness, liver dysfunction, renal dysfunction and malnutrition).
2.1.9 Cephalosporin in gonorrhea:
As antibiotic resistance is a big problem of today. Because of penicillin and tetracycline
resistance development in Neisseria gonorrheae, ceftriaxone is recommended now a day to treat
gonorrhea. However an oral alternative to parenteral ceftriaxone is needed. Cefixime, an oral
cephalosporin is also effective against resistant strains of gonococciand it has suitable
pharmacokinetics for single dose/day administration. Cefixime 400-800 mg orally given as once
a day is sufficient and effective as same as 250 mg dosage regimn of IM ceftriaxone for treating
uncomplicated gonorrhea (Handsfield et al., 1991).
2.2 Drug profile of cefixime:
Cefixime is a 3rd generation cephalosporin, which is active orally. It is a cell wall
synthesis inhibitor (Adam et al., 1995; Memon et al., 1997).
Cefixime has potent antibacterial activity with long duration of action and is well stable to beta -
lactamase (Arshad et al., 2009). Cefixime treats various infections which are caused by different
Gram +ve and Gram -ve microorganisms.It may be indicated in otitis media, gonorrhea, typhoid
and in certain respiratory and urinary tract infections (Baltimore, 2005). Cefixime is available in
different formulations in different strengths for both pediatric and adult patients. Tablets and
capsules of cefixime are available in 200 mg and 400 mg while oral suspension of it comprises
of 100 mg/5ml and 200 mg/5ml. The recommended dose for patients above the age of 12 years is
50
200-400 mg/day and below age of 12 years recommended dose is 100-200 mg/day (Baltimore,
2005).
2.2.1 Physicochemical properties of cefixime:
Cefixime, a cephalosporin antibiotic, is white to almost white, slightly hygroscopic
powder; it has good solubility in methanol and is sparingly soluble in anhydrous ethanol,
whereas in water it is slightly soluble and practically it is insoluble in the ethyl acetate (British
Pharmacopoeia (BP, 2011). Cefixime was marketed in the form of Tablets and suspensions for
oral use (Ali and Mohiuddin, 2012).
2.2.2 Structural description of cefixime:
Cefixime had molecular weight 453.4 and had molecular formula C16H15N5O7S2.
Penicillins and cephalosporinswere structurally and functionally related with each other because
they shared a common β- lactam ring. Cephalosporins were composed of a six member ring
having sulphur atom attached to a β-lactam. Most of the cephalosporins were derived from 7-
aminocephalosporic acid (Naqvi et al., 2011).
Cefixime is a third-generation oral cephalosporin of the amino thiazole antibiotic group.
It differs from the other oral cephem antibiotics structurally in that it has vinyl group in 3-
position of aminothiazolyl ring and a β-2- aminothiazolyl-4-y1- (α-aIkoximine) acetamide side
chain at 7-position of cephem molecule. This modification in structure always supports efficient
oral absorption and has stability against Gram +ve and Gram -ve bacteria. Fig 2.1 and Fig 2.2
describes the structural representation of cefixime and its trihydrate.
C-CO-NH ”'”
CH=CH- CH
COOH
Fig 2.1: Chemical structure of cefixime.
51
Molecular formula of cefixime is C16H15N5O7S2; molecular mass is 453.5 and the melting
point is 218-225°C (Moffat et al., 2011).
Fig 2.2: Chemical structure of cefixime tri-hydrate.
As the tri-hydrate, the molecular weight is 507.50 and the Chemical Formula as cefixime
tri-hydrate is C16H15N5O7S2·3H2O (Baltimore, 2005).
2.2.2.1 Systematic (IUPAC) name:
In the International Union of Pure and Applied Chemistry (IUPAC), chemically its name
could be represented as (6R, 7R)-7-{[2-(2-amino-1, 3-thiazol-4-yl)-2-(carboxymethoxyimino)
acetyl] amino}-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2 carboxylic acid (Reddy
and Reddy, 2012).
2.2.2.2 Structure activity relationship:
Chemically it was composed of a cephem nucleus that was attached to a six member ring
of dihydrothiazine. At position 3, cephem nucleus had a vinyl group for the absorption of intact
molecule through intestine and at 7-position acetic acid oxy- imine group and aminothiazole ring
were attached for antibacterial activity (Arshad et al., 2009).
52
2.2.3 Degradation and storage of cefixime:
Stability study of cefixime shows that cefixime is stable for 4 hours at short term room
temperature while stable for 16 hr at temperature of -20°C after preparation. Cefixime is stable
for 3 cycles of freeze and thaw, after storage at -20°C and then thawing at room temperature.
Stock solution of cefixime and internal standard is stable for 6 hr at room temperature and of 2
weeks at -20°C. In plasma, cefixime is stable for one month or more if stored at -20°C (Asiri et
al., 2005).
Regarding the degradation profile of cefixime, it was observed that 25% of cefixime was
degraded on heating at 80°C for 1 hr in 0.01 M NaOH. The drug was totally degraded if heated
for 4 hr at 80°C in 0.1 M NaOH. In acidic conditions, 25% of drug was degraded if heated with
0.01M HCl at 80°C for 2.5 hr. Degradation (100%) was observed at 80°C after 7 hr in 0.1M HCl.
The degradation was very rapid under oxidative conditions, as 25% drug was degraded if left at
25°C with 1% H2O2 in 3.5 hr (Gandhi and Rajput, 2009).
Tablets could be stored at room temperature for two years but suspension for 14 days
after reconstitution (Ali and Mohiuddin, 2012). The drug must be stored in a cool and dry place
and light should be avoided.
2.2.4 Pharmacological action of cefixime:
Cefixime is a cephalosporin antibiotic that acts as bacterial cell wall synthesis inhibitor,
cephalosporins are semi-synthetic antibacterial agents derived from a natural antibacterial
"cephalosporin-C", produced by a mould Cephalosporium acremonium.
Cephalosporins are classified to generations according to their antibacterial activity.
Succeeding generations generally have increasing activity against Gram -ve bacteria. Cefazolin,
cefradine, cefalexin and cefadroxil are commonly used first generation cephalosporins. Second
generation cephalosporins have similar activity to first generation against Gram +ve bacteria but
with greater activity against Gram -ve bacteria. Cefaclor and cefuroxime are classified as second
generation cephalosporins. The 3rd generation cephalosporins have more resistance to hydrolysis
by β-lactamases than other generations of cephalosporins and have a wider spectrum and greater
potency of activity against Gram-negative organisms.
53
Cefixime is effective against Enterobacteriaceae as well as against H. influenzae
(including strains having resistance to ampicillin), penicillin-susceptible Streptococcus
pneumonia, pathogenicNeisseria spp. (including gonococci having penicillin-resistance) and
certain Streptococcus species. Penicillin-resistant species include Staphylococcus spp.,
pneumococci, Enterococcus spp., Acinetobacter spp., Pseudomonas spp. and Listeria spp. Oral
cefixime is used to treat susceptible infectious diseases including pharyngitis, gonorrhoea, RTIs,
otitis media and infections of lower respiratory tract (Martindale, 2009).
For adults the dose of cefixime is 200 to 400 mg per day in single dose or two equally
divided doses. The dose recommended in children above 6 months is 8 mg/kg/day given as
single or two divided doses (BNF, 2011).
About 40-50% of cefixime in oral dose is absorbed from the GIT, either taken before
meal or after meals; however the rate of absorption of the drug may decrease due to food.
Absorption is fairly slow; peak plasma concentrations were reported between 2 to 6 hours
(Martindale, 2009).
Cefixime is effective in prophylaxis and treatment of biliary tract infections because
biliary excretion level of cefixime in bile is higher than other enterobacteriaceae family. The
level of cefixime is constant for 20 hours after giving single oral dose of 200 mg. This study was
conducted in patients with T-tube drainage for cefixime biliary excretion (Westphal et al., 1993).
The short-course cefixime therapy shows its effectiveness as other drug therapies (e.g.,
ofloxacin and amoxicillin) often used to treat infections of respiratory system, gonorrhea and
cystitis. In the treating community-acquired pneumonia, cefixime is effective as transitional
therapy, where by conversion of clinically stable patients from 3rd generation parenteral
cephalosporins to this agent results in the reduced direct and indirect both costs. So, in current
environment of health care in many countries, short course or transitional therapy with cefixime
is another advantage resulting in reduction of both indirect and direct costs (Quintiliani, 1996).
Infection of respiratory tract is one of the important and most common infectious disease
worldwide and in criticallyill patients in the developing countries RTI isthe leading cause of
morbidity and mortality (Navaneeth and Belwadi, 2002; Kumari et al., 2007).
Respiratoryinfections, in particular, those occurring in upper respiratory tract are seen with
54
greater frequency in adultsand have remarkable economic impact (Carroll and Reimer., 1996).
Cefixime is commonly used in upper respiratorytract infections (URTI). Some authors
recommendcefixime as first line antibiotic in community-acquiredURTI (Hedrick, 2010).
However, in some publications cefixime hasdemonstrated poor efficacy (Dreshaj et al., 2011).
Cefixime is frequently used to treat upper respiratory tract infections (URTI).
Therapeuticresponse of oral Tablet depends on its bioavailability. Cefixime has 40 to 50%
bioavailability due to its poor solubility (Nerurkar et al., 2013).
2.2.5 Antibacterial activity of cefixime:
Cefixime inhibits a wide range of Gram negative and Gram positive bacteria, especially
most of the members of family Enterobacteraceae, including the strains that produce the plasmid
mediated Beta-lactamases. The poor activity is reported against enterococci, Pseudomonas
aeruginosa, Staphylococcus aureus and anaerobes (Counts et al., 1988).
Cefixime shows broad spectrum actions against Gram +ve and Gram -ve aerobic bacteria
including Proteus vulgaris, Proteus mirabilis, Providencia stuartii, Haemophilus influenza,
Branhanella catarrhalis, Streptococcus pneumonias, Escherichia coli, Neisseria gonorrhoeae,
N. meringitidis, Klebsiella pneumoniaeandK. oxytoco (Brittain et al., 1985; Fuchs et al., l986;
Pfeffer et al., 1987). It is used to treat otitis media in children also (Risser et al., 1987) and adults
(Irvani et al., 1988; Kiani et al., 1988) and also is effective in treatment of typhoid fever (Bhutta
et al., 1994; Girgis et al., l995a,b; Malik et al., 1998; Rabbani et al., 1998; Cao et al., 1999).
Cefixime is also effective against Streptococcus pyogenes, S. pneumoiae and S. agalactiae. Most
strains of Streptococci belonging to the Lancefield group-F and G are only moderately sensitive
whereas Staphylococcus aureus, S. epidermidis, Enterococcus faecalis, Listeria monocytogenes,
Pseudomonas aeruginosa, P. cepacia, P. multophilia, Campylobacter jejuni and Bacteriodes spp
are generally resistant (Neu, 1988).
2.2.6 Route of administration and dosage of cefixime:
Cefixime is an oral antibiotic, readily absorbed from the gastrointestinal tract of both
adult and pediatricpatients; Cefixime can be administered to adults either as once daily dose of
400 mg or divided into twice-daily doses. A lower dosage of 200 mg daily has been used in
uncomplicated urinary tract infections. In pediatric patients, cefixime can be administered at a
55
dose of 4-8 mg/Kg as a single or twice daily dose. In patients of severe renal dysfunction
(creatinine clearance < 20m1/min), half of the standard dose of cefixime should be given once a
day (Francis et al., 1987). The recommended oral dosage in Japan is 100-200 mg/day in adult
and 3-6 mg/Kg for children, in twice daily doses, however in severe or non-responding
infections; the dose may be increased for adults up to 400 mg and for the children up-to l2
mg/Kg in twice daily doses.
2.2.7 Mode of action of cefixime:
Bactericidal activity of β-lactams (penicillin and cephalosporin) depends on the active
growth of those bacteria which will actively synthesize new cell walls. Cefixime inhibits the
synthesis of bacterial cell wall (that is essential for their growth and development).
Cefixime, a third generation cephalosporin and orally active drug is a cell wall synthesis
inhibitor (Memon et al., 1997). Cell wall protects the bacteria in unfavorable environmental
condition. Without cell wall bacteria were susceptible to environment and could die (Brahmaiah
et al., 2013). Cefixime performed its antibacterial activity by binding with penicillin-binding
proteins that were present in cell wall (Bhagawati et al., 2005).
2.2.8 Adverse effects of cefixime:
Adverse effects reported clinically in cefixime treated patients have usually been
transient and mild to moderate in case of severity. Diarrhea and some stool changes (soft stool
and loose stools, as distinguished front diarrhea), abdominal pain and nausea are the most
frequent adverse effects reported in adults and neonates or children administered once and twice
a day (Brogden and Campoli-Richards, 1989; Leggett et al., 1990). Cefixime suppressed the
Helicobacter pylori which mostly cause the recurrence of the gastric ulcer (Tatsuta et al., 1990).
Cefixime at highest concentration cause headache, rashes, dizziness and gastrointestinal
side effects (Azmi et al., 2013). It was reported that cephalosporin had convulsive activity to
some extent. It was caused by suppressing the inhibition of postsynaptic response that was
facilitated by gamma amino butyric acid receptor (Sugimoto et al., 2003).
Anaphylactic reactions (like shock and fatalities) have been observed by using cefixime.
Patient in whom some form of allergy, particularly to drugs, has demonstrated, antibiotics such
56
as cefixime should be given with caution. Treatment with cefixime or other broad spectrum
antibiotics may alter colon's normal flora and may cause overgrowth of the clostridia. Some
studies indicate that severe antibiotic associated diarrhea particularly Pseudomembranous colitis
is primarily caused by a toxin produced by Clostridium difficile (Baltimore, 2005).
2.2.8.1 Mutagenesis, carcinogenesis, impairment of fertility:
Lifetime studies have not been conducted to evaluate carcinogenic potential in animals.
Cefixime did not cause mutation in mammalian cells or bacteria, DNA or chromosomal damage
in the mouse micronucleus test. Cefixime did not affect fertility and reproductive performance in
rats, at doses up to 125-times the adult therapeutic dose (Baltimore, 2005).
2.2.9 Use of cefixime in mothers and children:
There are very few studies or data available on the use of cefixime in females and in
small age groups in human or trials in other animals.
2.2.9.1 Use in pregnant and nursing mothers:
2.2.9.1.1 Use in pregnancy:
For studies on pregnancy and reproduction, cefixime was administered in rats and mice at
400 times the greater dose than human dose and no harmful effects to fetus were revealed.
However no well-controlled and adequate studies have been performed in pregnant women.
During pregnancy cefixime should be given only if it is needed clearly, as studies on animals are
always not the prediction for human response (Baltimore, 2005).
In another study cefixime was used in pregnant woman for treatment of gonorrhea by
giving 400 mg single dose orally and cefixime was found a safe drug and can be used in
pregnancy for gonorrhea with better results (Miller, 1997).
2.2.9.1.2 Delivery and labor:
Cefixime is not studied for administration in delivery and labor. Treatment should only
be given if needed clearly (Baltimore, 2005).
2.2.9.1.3 Nursing mothers:
57
Excretion of cefixime in human milk is not clearly known. During treatment with
cefixime, nursing should be discontinued temporarily (Baltimore, 2005).
2.2.9.2 Use in pediatrics:
Cefixime has not been studied in children below 6 months of age for effectiveness and
safety of the drug. GIT adverse effects such as loose stools and diarrhea have been observed in
pediatric patients who have received the cefixime suspension, similarly as seen in the adults
receiving cefixime Tablets (Baltimore, 2005).
2.2.9.2.1 Role of cefixime in pediatric UTI:
Cefixime is highly effective against a broad range of Gram -ve and some Gram +ve
aerobic bacteria. In urine of children it attains a bactericidal concentration. Cefixime was only
found oral antibiotic used alone for serious forms of UTIs such as acute pyelonephritis. The drug
is used as a mono-therapy, 8 mg/kg dose as single or 12-hourly divided 2 doses for 14 days;
double dose on very 1st day of therapy. Alternatively, an intravenous antibiotic may be given for
first 3 days later on oral cefixime administration for remaining 11 days (switch-therapy). So, it is
concluded that cefixime is effective equally or more than other usual treatments for
uncomplicated UTIs, having low rate of adverse events. Various studies done across the world
indicated in their results that cefixime may be used in children as mono-therapy or as a switch-
therapy for treatment of uncomplicated UTI (Rao, 2005).
2.2.10 Use of cefixime as switch therapy:
Switching from parenteral to oral antimicrobials is successful technique in treating many
serious infections. Switch therapy results in significant cost saving also. Moreover it shortens the
stay in hospitals. Cefixime shows similar activity to ceftriaxone and cefotaxime sensitive
becteria with except of Staphylococcus aureus and penicillin-resistant Streptococcus
pneumoniae. It shows excellent tissue penetration and prolongs half- life resulting once-a-day
dosing of the drug. All these properties support the cefixime as switch therapy when a sensitive
pathogen is identified (Low, 1995).
58
2.2.11 Cefixime preparations in Pakistan:
It is important to compare different dosage forms, routes of drug administration and
preparations of various manufacturers. As therapeutic effects of antibiotics are mediated by their
access to the sites of action (target tissues) which is governed by rate and extent (completeness)
of absorption of a drug from its site of administration or bioavailability in biological system
(Gibaldi, 1984). Administration of different dosage forms of ampicillin using different routes in
sheep showed different bioavailability and pharmacokinetic parameters (Ahmad, 1984 and
Hafeez, 1985).
Cefixime is available in market of Pakistan in different dosage forms; routes and
preparations/formulations manufactured by different manufacturers and each manufacturing
company claim the superiority of their own product. These claims and increasing use of cefixime
in modern practice necessitates the assessment of bioavailability of these preparations.
There are a number (hundred plus) of brands of cefixime in market of Pakistan
manufactured by different manufacturers with different potencies, dosage forms, routes and
prices. Some of these brands (of famous companies) are listed below in the Table 2.2.
Table 2.2: Different brands of cefixime available in Pakistan.
Sr # Brand
Name
Manufacturer Dosage
Form
Potency Pack
Size
Route Retrail
Price
(Rs.)
1 Arocef Raazee Capsule
Suspension
400 mg
100 mg
200 mg
5's
30 ml
30 ml
Oral
-
-
249.00
119.00
150.00
2 Caricef Sami Capsule
Suspension
400 mg
100 mg
100 mg
200 mg
5's
30 ml
60 ml
30 ml
Oral
-
-
-
375.00
130.00
198.00
210.00
3 Cebosh Bosch Tablet 200 mg 10's Oral 230.00
59
Capsule
Suspension
400 mg
400 mg
100 mg
100 mg
200 mg
5's
5's
30 ml
60 ml
30 ml
-
-
-
-
-
235.00
235.00
120.00
190.00
190.00
4 Cef-OD CCL Tablet
Capsule
Suspension
200 mg
400 mg
100 mg
100 mg
200 mg
10's
5's
30 ml
60 ml
30 ml
Oral
-
-
-
-
210.00
245.00
115.00
199.00
199.00
5 Cefexol Nabiqasim Capsule
Suspension
400 mg
100 mg
200 mg
5's
30 ml
30 ml
Oral
-
-
225.00
125.00
199.00
6 Cefiget Getz Tablet
Capsule
Suspension
200 mg
400 mg
100 mg
200 mg
10's
5's
30 ml
30 ml
Oral
-
-
-
200.00
295.00
125.00
209.00
7 Cefim Hilton Capsule
Suspension
200 mg
200 mg
400 mg
100 mg
100 mg
200 mg
10's
5's
5's
30 ml
60 ml
30 ml
Oral
-
-
-
-
-
275.00
120.00
315.00
145.00
230.00
230.00
8 Cefix Standpharm Capsule
Suspension
200 mg
400 mg
100 mg
100 mg
200 mg
5's
5's
30 ml
60 ml
30 ml
Oral
-
-
-
-
123.50
250.00
123.53
183.60
183.60
9 Ceforal-3 Zafa Capsule
Suspension
400 mg
100 mg
5's
30 ml
Oral
-
160.00
95.00
10 Cefspan Barrett Capsule 400 mg 5's Oral 512.51
60
Hodgson Suspension 100 mg
200 mg
30 ml
30 ml
-
-
286.00
350.00
11 Ceftas Platinum Capsule
Suspension
200 mg
400 mg
100 mg
200 mg
5's
5's
30 ml
30 ml
Oral
-
-
120.00
240.00
130.00
195.00
12 Efix Highnoon Capsule
Suspension
400 mg
100 mg
5's
30 ml
Oral
-
250.00
120.00
13 Evofix Pharmevo Capsule
Suspension
400 mg
100 mg
100 mg
200 mg
5's
30 ml
60 ml
30 ml
Oral
-
-
-
470.00
115.00
170.00
170.00
14 Maxpan Indus Capsule
Suspension
200 mg
400 mg
100 mg
200 mg
10's
5's
30 ml
30 ml
Oral
-
-
-
186.30
186.30
105.80
197.80
15 Omixim Searle Capsule
Suspension
200 mg
400 mg
100 mg
200 mg
5's
5's
30 ml
30 ml
Oral
-
-
-
165.00
325.00
130.00
220.00
16 Tycef Helix Capsule
Suspension
400 mg
100 mg
100 mg
200 mg
5's
30 ml
60 ml
30 ml
Oral
-
-
-
225.00
115.00
190.00
185.00
17 Waybac Woodwards Capsule
Suspension
200 mg
200 mg
400 mg
100 mg
200 mg
10's
5's
5's
30 ml
30 ml
Oral
-
-
-
274.94
165.00
275.00
125.00
217.00
18 Xival Siza Capsule
Suspension
400 mg
100 mg
5's
30 ml
Oral
-
249.00
129.00
61
100 mg 60 ml - 169.00
19 Y-fix Adamjee Capsule
Suspension
400 mg
100 mg
100 mg
5's
30 ml
60 ml
Oral
-
-
141.17
70.58
111.76
20 Zylofixim Remington Suspension 100 mg
200 mg
30 ml
30 ml
Oral
-
120.00
190.00
2.3 Biopharmaceutical character of cefixime:
Biopharmaceutic is the branch of pharmaceutics in which influence of the formulation on
therapeutic effects of a drug product are studied. Biopharmaceutic deals with the study of
bioavailability, pharmacokinetics and co-relation within and in between In-vitro and In-vivo
parameters of drug (Parveen, 1982).
2.3.1 Disposition kinetics:
Drug disposition is the description of the simultaneous effects of the drug distribution and
its elimination. After intravenous injection, drug levels in plasma are initially high and rapidly
decline mono-phasically or in some cases poly-phasically. The validity and utility of
bioavailability measurements of any drug depends upon its pharmacokinetic behavior in body.
Pharmacokinetics is a discipline that deals with the study and mathematical characterization of
the time course of absorption (bioavailability), distribution, biotransformation and excretion of
drug products and its metabolites in the body, as well as relationship of these processes to
intensity and the time course of therapeutics and toxicology of the drugs (Parveen, 1982).
2.3.2 Pharmacokinetics models:
The course of mathematical characterization and evaluation of the relationship mentioned
above necessitate different styles or models to design the experiment and to process and interpret
the resultant data. Many different models presented in literature may conveniently be divided
into simple physiologic and pharmacological models out of which simple further may be
classified into two, linear and non-linear, broad categories of models. Linear models are widely
62
used for pharmacokinetics characterization and are good enough to explain the kinetic behavior
of most of the drugs (Parveen, 1982).
Pharmacokinetics is the mathematical description of the changes of concentration of
drugs within an organism. A common approach to study the pharmacokinetic behavior of drugs
is to depict the body as a system of compartments. In many instances these components which
are mathematical entities, have no physiological meaning, but are useful in describing the
disposition kinetics of a drug. A one compartment system is defined as one in which the drug
which enters the body is instantaneously distributed into the available spaces. The one
compartment model is useful for description of the time course of drugs in the plasma or urine,
after oral dose or intramuscular administration of the drugs. When distribution in-between the
central and the peripheral compartment are slow relative to elimination, it represents a two
compartment model. The two compartment open model accurately describes the
pharmacokinetics of most drugs after intravenous administration (Ahmad, 1983).
The extent of bioavailability and kinetic behavior plays a dominant role in selecting the
most promising antibiotics and determining the optimal treatment intervals (Ziv, 1975).
The concept of half life during the evaluation of disposition kinetics of drugs was first
introduced by Dost, (1949). It is widely used parameter and is a function of the system including
the constant of distribution, biotransformation and renal excretion of unchanged drug (Wagner
and Northham, 1967).
2.3.3 Bioavailability:
Human and animal life is constantly exposed to diverse type of chemicals deliberately or
accidently added to the environment and are found as pollutant. These chemicals range from
motor vehicles exhausts to industrial effluent, food additives, pesticides, insecticides and
pharmaceutical agents. The environmental pollutants may gain access to body directly or
indirectly through food chain. Human beings are exposed to a variety of chemicals for the
treatment of ailments. Domestic animals are intentionally given feed additives, veterinary drugs
and compounds for production improvement or protection by the insecticides or disinfectants.
All these compounds may pose a potential risk to animals if present in excessive concentrations.
The residues of all these chemical compounds may pass in the edible products from animals or
63
poultry and may cause a serious human health risk for consumers. Therefore the bioavailability
of such antibiotics to treat different infectious diseases is of basic importance for evaluation of
their beneficial or toxic effects (Butt, 1996).
Bioavailability is described as the rate and relative concentration of drug reaching the
general blood circulation. It may also be the extent of absorption of drug following its
administration by routes other than intravenous administration. Bioavailability is one of the the
certain factors that determine the relationship between the intensity of action and the drug
dosage. Different factors influencing the bio-availability include the first pass hepatic
biotransformation, solubility, chemical instability of the drug and nature of the drug formulation.
Moreover the factors that modify the absorption of a drug can change its bio-availability
(Baggot, 1977).Bioavailability (rate and extent of the absorption from a drug dosage form) is
reflected by the concentration-time curve of the administrated drug in systemic circulation.
Certain chemically equivalent drugs have produced clinically important and measurable
differences in the therapeutic effect which are the result of differences in bioavailability. Not
only bioequivalence has been found in products of different manufactures but there also have
been substantial variations in the bioavailability of different batches from the same company
(Parveen, 1982).Bioavailability parameters of 1st, 2nd, 3rd and 4th generation cephalosporins in
human being and in animals have been tabulated in Table 2.3.
64
Table 2.3: Reported values of some bioavailability parameters of cephalosporins in human beings.
Cephalosporin
Subjects
Dose
Route
Bioavailability Parameters
Reference
mg
mg
per
kg
maxC maxT AUC AUMC MRT
µg/ml hr µg.hr/ml /ml2µg.hr hr
Cephalexin Cats - 10
IV
- - - - 2.11
Albarellos et
al., 2011
Cefixime Children - - - 2.7 - - - - Alshare, 1999
Cefixime Children - - - 3.7 - - - - Alshare, 1999
Cefixime Children - - - 4.4 - - - - Alshare, 1999
Cefepime
Patients with
cystic
fibrosis - - - 141.3 - 1.73 - -
Ambrose et
al., 2002
Cefepime
Patients
(LRTIs)
- - - 71.2 - 3.92 - -
Ambrose et
al., 2002
Cefepime
Sepsis
- - - 94.2 - 3.42 - -
Ambrose et
al., 2002
Cefepime Young - - - 75.1 - 2.26 - -
Ambrose et
al., 2002
Cefepime Elders - - - 74.4 - 3.05 - - Ambrose et
65
al., 2002
Cefixime Healthy male
200
mg/10ml - Oral 3.38 4 26.5 - -
Asiri et al.,
2005
Cefixime -
200
mg/10ml - Oral 3.45 4 27.5 - -
Asiri et al.,
2005
Cefixime - 200 - Oral Tablet 2 - - - -
Baltimore,
2005
Cefixime - 400 - Oral Tablet 3.7 - - - -
Baltimore,
2005
Cefixime - 200 - Oral suspension 3 - - - -
Baltimore,
2005
Cefixime - 400 - Oral suspension 4.6 - - - -
Baltimore,
2005
Cefixime Young
400 mg OD
for 5 days - - 4.74 3.9 34.9 - -
Baltimore,
2005
Cefixime Elderly
400 mg OD
for 5 days - - 5.68 4.3 49.5 - -
Baltimore,
2005
Cefepime
Human
subjects 250 -
IV
16.3 - 34 - 2.3
Barbhaiya et
al., 1990c
Cefepime - 500 -
IV
31.6 - 62 - 2
Barbhaiya et
al., 1990c
Cefepime - 1000 - IV 66.9 - 137 - 2.2 Barbhaiya et
66
al., 1990c
Cefepime
(Young)
males 1000 -
IV
75.1 - 149 - 2.32
Barbhaiya et
al., 1992b
Cefepime
Young
females
- -
IV
90.1 - 172 - 2.24
Barbhaiya et
al., 1992b
Cefepime
(Elderly)
male
- -
IV
74.4 - 199 - 3.5
Barbhaiya et
al., 1992b
Cefepime
(Elder)
females
- -
IV
83.5 - 218 - 3.3
Barbhaiya et
al., 1992b
Cefprozil Fasting 250 - Oral 6.13 1.2 15 - 2.45
Barbhayia et
al., 1990
Cefaclor With food 250 - Oral 8.7 0.6 8.6 - 1.28
Barbhayia et
al., 1990
Cefprozil Fasting 250 - Oral 5.27 2 14.9 - 2.99
Barbhayia et
al., 1990
Cefaclor With food 250 - Oral 4.29 1.3 7.57 - 2.06
Barbhayia et
al., 1990
Cefprozil
Healthy male
volunteers 250 - Oral 6.1 1.5 16.1 - 2.6
Barbhayia et
al., 1990a
67
Cefaclor
Healthy male
volunteers 250 - Oral 10.6 0.5 8.7 - 1
Barbhayia et
al., 1990a
Cefprozil
Healthy male
volunteers 500 - Oral 11.2 1.4 32 - 2.7
Barbhayia et
al., 1990a
Cefaclor
Healthy male
volunteers 500 - Oral 17.3 0.7 17.5 - 1.2
Barbhayia et
al., 1990a
Cefprozil Humen 250 - Oral 6.1 1.5 16.4 - 2.7
Barbhayia et
al., 1990b
Cefprozil - 500 - Oral 10.5 1.5 31.1 - 2.7
Barbhayia et
al., 1990b
Cefprozil - 1000 - Oral 18.3 2 61.2 - 3.1
Barbhayia et
al., 1990b
Cefprozil
Beagle dogs 125 -
IV
77.6 - 7043 - 110
Barbhayia et
al., 1992a
Cefprozil
Beagle dogs 125 -
Oral
26.6 - 5572 - 183
Barbhayia et
al., 1992a
Cefixime Dogs
- 6.25
IV
- - 5.2 0.312 -
Bialer et al.,
1987
Cefixime Dogs
- 25
IV
- - - - -
Bialer et al.,
1987
Cefpodoxime Healthy adult 100-400 -
Oral
1-4.5
1.9-
3.1 - - - Borin, 1991
68
Cefoperazone Neonates 50 - 136 - - - -
Bosso et al.,
1983
Ceftriaxone
Healthy
volunteers 2000 -
IV
239 0.5 1459 - -
Bourget et
al., 1993
Ceftriaxone
Pregnant
women 2000 - Infusion 224.3 1 1588 - -
Bourget et
al., 1993
Cefixime
Normal
subjects 50 - - 1 - 7 - -
Brittain et al.,
1985
Cefixime - 100 - - 1.5 - 11 - -
Brittain et al.,
1985
Cefixime - 200 - - 2.6 3.4 23 - -
Brittain et al.,
1985
Cefixime - 400 - - 3.9 4.3 36 - -
Brittain et al.,
1985
Cefixime
Healthy
subjects 200 - -
2.0-
2.6
3.0-
4.0 - - -
Brogden and
Campoli-
Richards,
1989
Cefepime Neonates - 50 - 0.89 - - - -
Capparelli et
al., 2005
Cefoperazone Calves - - - - - - - 1.43
Carli et al.,
1986
69
Cefoperazone
In women 2-
3 days after
postpartum 1000 -
IV
- - 177.61 - -
Charles and
Bryan, 1986
Cefotaxime
1000 -
IV
- - 30.22 - -
Charles and
Bryan, 1986
Cefpodoxime Healthy adult 400 - Oral 3.8 - - - -
Chugh and
Agrawal,
2003
Ceftolozane
Neutropenic
mice - 25 - 25.2 0.25 13.3 - -
Craig and
Andes, 2013
Ceftolozane - - 100 - 110 0.25 55.5 - -
Craig and
Andes, 2013
Ceftolozane - - 400 - 574 0.25 299 - -
Craig and
Andes, 2013
Cefoperazone
Healthy male
and female
adult 2000 -
IV
288.9 - 1215.9 - -
Deeter et al.,
1990
Cefotaxime
- 2000 -
IV
132.7 - 182 - -
Deeter et al.,
1990
Ceftriaxone
- 2000 -
IV
261.6 - 3144.4 - -
Deeter et al.,
1990
Ceftazidine - 2000 - IV 167.3 - 409.2 - - Deeter et al.,
70
1990
Ceftizoxime
- 2000 -
IV
205.2 - 516.4 - -
Deeter et al.,
1990
Cefixime
Normal
subjects 200 - Oral 2.5 2.83 - - -
Dhib et al.,
1991
Cefixime
Uremic
patients 200 - Oral 2.83 - - - -
Dhib et al.,
1991
Ceftazidime Healthy adult 2000 - - 69-90 - - - -
Drusano et
al., 1984
Cefixime - 200 - Oral Tablet 2.5 3.7 18 - -
Duverene et
al., 1992
Cefixime - 200 - IV injection - - 58 - -
Duverene et
al., 1992
Cefixime Sheep - - - 0.63 - 6.88 - -
Eldalo et al.,
2004
Cefixime Cattle - - - 0.5 - 8.98 - -
Eldalo et al.,
2004
Cefazolin
In parturients
undergoing
cesarean
surgery 2000 - - - - 436 - -
Elkomy et
al., 2014
Cefixime Healthy 200 - IV solution - - 47 - - Faulkner et
71
volunteers al., 1988
Cefixime
Healthy
volunteers 200 - Oral solution 3.2 - 26 - -
Faulkner et
al., 1988
Cefixime
Healthy
volunteers 200 - Oral capsule 2.9 - 24 - -
Faulkner et
al., 1988
Cefixime
Healthy
volunteers 400 - Oral capsule 4.8 - 39 - -
Faulkner et
al., 1988
Cefixime Healthy male 400 - Oral suspension 4.67 - - - -
Faulkner et
al., 1989
Cefixime - 400 -
Oral suspension
4.1 - - - -
Faulkner et
al., 1989
Cefixime
Healthy male
subjects 400 -
Oral suspension
4.67 - - - -
Faulkner et
al., 1989
Cefixime - 400 -
Oral suspension
4.1 - - - -
Faulkner et
al., 1989
Cefixime - 400 - Oral solution 4.27 - - - -
Faulkner et
al., 1989
Ceftriaxone
Calves
(buffalo) - 10
IV
- - 40 - -
Gohil et al.,
2009
Ceftriaxone
Calves
(buffalo) - 10 IM 16 - 30 - -
Gohil et al.,
2009
Ceftazidime Female - 10 IV - - 209.74 - 3.96 Goudah and
72
dromedary
camels
Sherifa, 2013
Ceftazidime - -
10
IM - - 195.23 - 4.84
Goudah and
Sherifa, 2013
Cefepime
Healthy
rabbits - - IM 114.9 0.5 300.2 1099.1 3.65
Goudah et
al., 2006
Cefepime
Febrile
rabbits - - IM 130.4 0.6 646.9 2915.5 4.56
Goudah et
al., 2006
Cefotaxime Neonates - 25 - 171 - - -
Gouyon et
al., 1990
Cefixime
Healthy
subjects 400 - Oral 4.9 4.9 40 - -
Guay et al.,
1986
Cefoperazone
Cross bred
calves - 4
IV
- - 29 46.3 1.6
Gupta et al.,
2007
Cefoperazone
Cross bred
calves - 20 IM 9.76 0.75 15.7 56.6 3.62
Gupta et al.,
2008
Cefixime
Healthy
subjects 400 - Oral 4.9 4.9 40 - -
Guay et al.,
1986
Cefixime
Healthy adult
male 400 - Oral 4.9 4 38 - -
Healy et al.,
1989
Cefuroxime
Malnourished
rats - 2.2
Oral
- - - - 73.2
Hernandez et
al., 2008
73
Cefuroxime
Controlled
rats
- 2.2
Oral
- - - - 63
Hernandez et
al., 2008
Cefixime
Healthy
volunteers 400 - - 2.2 - 26 - 7.47
Jieying et al.,
1996
Cefepime
Febrile
buffalo
calves - 10
IV
- - 101 - -
Joshi and
Suresh, 2009
Cephalexin Healthy adult 1000 - Oral 23.4 - - - -
Kalman and
Steven, 1990
Cefadroxil Healthy adult - - Oral 13.7 - - - -
Kalman and
Steven, 1990
Cephradine Healthy adult 1000 - Oral 21.3 - - - -
Kalman and
Steven, 1990
Cephalothin Healthy adult 1000 - Parenteral-IV 30 0.25 - - -
Kalman and
Steven, 1990
Cephapirin Healthy adult 1000 - Parenteral-IV 67 0.25 - - -
Kalman and
Steven, 1990
Cefazolin Healthy adult 1000 - Parenteral 188 0.25 - - -
Kalman and
Steven, 1990
Cefuroxime Healthy adult 1000 - Oral 6.3 - - - -
Kalman and
Steven, 1990
74
Cefuroxime Healthy adult 1000 - Parenteral 38-64 - - - -
Kalman and
Steven, 1990
Cefamandole Healthy adult 1000 - Parenteral 139 - - - -
Kalman and
Steven, 1990
Cefoxitin Healthy adult 1000 - Parenteral 125 - - - -
Kalman and
Steven, 1990
Cefmetazole Healthy adult 1000 - Parenteral 130 - - - -
Kalman and
Steven, 1990
Cefotetan Healthy adult 1000 - Parenteral
79-
132 - - - -
Kalman and
Steven, 1990
Cefaclor Healthy adult - - Oral 13.1 - - - -
Kalman and
Steven, 1990
Cefdinir Healthy adult 300 - Oral 2
2.0-
4.0 - - -
Kalman and
Steven, 1990
Cefoperazone Healthy adult 1000 -
IV
153 - - - -
Kalman and
Steven, 1990
Cefotaxime Healthy adult 1000 -
IV
102 - - - -
Kalman and
Steven, 1990
Ceftizoxime Healthy adult 1000 -
IV
85 - - - -
Kalman and
Steven, 1990
Ceftriaxone Healthy adult 1000 -
IV
150 - - - -
Kalman and
Steven, 1990
75
Ceftazidime Healthy adult - - Parenteral 69 - - - -
Kalman and
Steven, 1990
Cefixime Healthy adult 400 - Oral 4.8 - - - -
Kalman and
Steven, 1990
Cefroxadine Healthy adult - - - 17.62 1.44 - - -
Kang et al.,
2006
Cefadroxil Healthy adult 500 - - 16.04
1.5-
2.0 - - -
Kano et al.,
2008
Cefuroxime
Healthy
volunteers 500 - Oral 5.24 1.68 15.6 - 2.78
Kaza et al.,
2012
Cefuroxime
Healthy
volunteers 500 - Oral 4.86 1.78 15.1 - 2.89
Kaza et al.,
2012
Cefixime
Healthy male
and female
volunteers 200 - Oral Tablet 2.95 3.46 20.89 - -
Kees et al.,
1990
Cefixime - 200 - Oral syrup 2.43 3.42 17.83 - -
Kees et al.,
1990
Cefixime - 200 - Oral suspension 3.41 3.33 25.84 - -
Kees et al.,
1990
Cefixime
Healthy
volunteers 200 - Oral Tablet 3
3.3-
3.5 20.9 - -
Kees et al.,
1990 and
Kees and
76
Naber, 1990
Cefixime - 200 - Oral syrup 2.4
3.3-
3.5 17.8 - -
Kees et al.,
1990 and
Kees and
Naber, 1990
Cefixime - 200 -
Oral dry
suspension 3.4
3.3-
3.5 25.8 - -
Kees et al.,
1990 and
Kees and
Naber, 1990
Cefixime Healthy male 200 - Oral Tablet 3.38 4.7 - - -
Lan-Ying et
al., 2004
Cefixime - 200 - Oral capsule 3.29 4.6 - - -
Lan-Ying et
al., 2004
Cefixime - 200 -
(Domestic)
capsule 2.97 3.39 25.9 - -
Lei et al.,
2003
Cefixime - 200 -
(Imported)
capsule 2.83 3.33 24.7 - -
Lei et al.,
2003
Cefixime
Renal
patients
200 mg BD
for 2 days - - 3.4 - - - -
Leroy et al.,
1995
Cefaclor
Female
subjects 500 - Oral with water 13.4 1.25 21.2 - -
Li et al.,
2009
Cefaclor Female 500 - Oral with juice 11.7 1.5 20.5 - - Li et al.,
77
subjects 2009
Cefpodoxime - 400 -
Oral
3.9 3.1 22.4 130.3 5.7
Liu et al.,
2005
Cefixime - 400 -
Oral
3.4 4.8 25.6 164.2 6.5
Liu et al.,
2005
Cefixime Chinese men 400 - - 6 5.2 - - -
Liu et al.,
2007
Cefixime - - - - - 2 - - - Low, 1995
Cefixime
Renal
patients 100 - - 2 6 - - -
Maeda et al.,
1986
Ceftriaxone Calves (cow) - 10
IV
- - 57 - -
Maradiya et
al., 2010
Ceftriaxone Calves (cow) - 10 IM 15 - 28 - -
Maradiya et
al., 2010
Ceftriaxone
Cardiac
patients 1000 -
IV
- - 853 - 15
Martin et al.,
1996
Cefepime Mice - 80 - 90 - 75.7 - 0.58
Mathe et al.,
2006
Ceftriaxone Healthy adult 1000 - IM 79 1.5 - - -
Meyers et al.,
1983
Ceftolozane
Females /
males 500 - - 42.6 1 98.6 - -
Miller et al.,
2012
78
Cefixime
Healthy
volunteers 200 - Oral Tablet 2.61 3.49 19.4 - -
Ming-Hui,
2009
Cefixime - 200 - Oral capsule 2.81 3.31 21.2 - -
Ming-Hui,
2009
Cefixime - 200 - Oral 2.56 3.17 19.9 - -
Min-Ji et al.,
2004
Cefixime - 200 - Oral 2.32 3.5 19.1 - -
Min-Ji et al.,
2004
Cephalexin
Healthy male
and female
volunteers 500 - - 23.84 0.98 39.14 - 1.89
Mircioiu et
al., 2007
Cephalexin
Healthy
volunteers 500 - - 19.05 1.05 32.46 65.12 1.93
Mohamed et
al., 2011
Cephalexin
Healthy
volunteers 500 - - 17.36 1.1 33.35 72.46 2.04
Mohamed et
al., 2011
Cephalexin
Healthy
volunteers 500 - - 17.31 1.1 31.32 65.64 1.98
Mohamed et
al., 2011
Ceftazidime Dogs -
20 IV
- - 119 - 1.31
Monfrinotti
et al., 2009
Ceftazidime - -
25
IM - - 202 - 2.2
Monfrinotti
et al., 2009
Ceftazidime - - 25 SC - - 156 - 2.95 Monfrinotti
79
et al., 2009
Cefixime
Healthy male
volunteers 200 - Oral 3.3 4 - - -
Montay et al.,
1989
Cefixime
Healthy male
volunteers 400 - Oral 4.4 4 34 - -
Montay et al.,
1991
Cefixime Children - 1.5 - 0.6 4 4.1 - -
Motohiro et
al., 1986
Cefixime Children - 3 - 1.2 4 8.3 - -
Motohiro et
al., 1986
Cefixime - 50 - Oral granules 1.26 4 9.63 - -
Motohiro et
al., 1986
Cefixime - 50 - Oral capsule 1.16 4 7.82 - -
Motohiro et
al., 1986
Ceftriaxone Neonates - 50 - 153 - - - -
Mulhall et
al., 1985
Cefixime
Healthy
volunteers 50 mg bid - - 0.7 - - - -
Nakashima et
al., 1987
Cefixime
Healthy
volunteers 100 mg bid - - 1.2 - - - -
Nakashima et
al., 1987
Cefixime
Healthy
volunteers 200 mg bid - - 2.1 - - - -
Nakashima et
al., 1987
Cefixime - 200 - - 2.5 3 - - - Nies, 1989
80
Ceftriaxone Humen
water
asdiluent - IM 44.6 2.5 578 - -
Patel et al.,
1982
Ceftriaxone -
lidocain
asdiluent - IM 41.9 3 577 - -
Patel et al.,
1982
Cefepime Calves - 5
IV
- - 47.73 190.3 3.95
Patel et al.,
2006
Cefepime Cow (calves) - 5
IV
- - 48 - -
Patel et al.,
2006
Cefepime Cow (calves) - 5 IM 8.6 - 47 - -
Patel et al.,
2006b
Cefepime Sheep - 20
IV
- - 136 - -
Patel et al.,
2010
Cefepime Sheep - 20 IM 26 - 141 - -
Patel et al.,
2010
Cefepime Goat - 10
IV
- - 78 - -
Patni et al.,
2008
Cefepime Goat - 10 IM 16 - 93 - -
Patni et al.,
2008
Cefpodoxime
Male and
female
subjects 200 - Oral 3.03 3.67 33.3 - -
Peter et al.,
1992
Ceftriaxone Males and 2000 - IV 306 0.5 155.7 - 9.1 Pletz et al.,
81
females 2004
Cefpirome
Buffalo
calves - 10 IM 9.04 0.5 28.7 107.7 3.76
Rajput et al.,
2007
Cefpirome
Crossbred
calves - 10 IM 10.1 0.75 31.7 105.1 3.31
Rajput et al.,
2012
Cefoxitin Neonates - 30 - 69.8 - - - -
Regazzi et
al., 1983
Cefuroxime Neonates - 10 - 24.2 - - - -
Renlund and
Pettay, 1977
Cefixime - 400 - Oral 4 - - - -
Robert et al.,
2001
(Bioxime)
Cefuroxime
Healthy
volunteers 500 - Oral 5.562 1.78 17.308 - -
Sabati et al.,
2014
(Zinnat)
Cefuroxime
Healthy
volunteers 500 - Oral 6.044 1.76 18.13 - -
Sabati et al.,
2014
Cefotaxime Bufalo calves - 13 - - - 18.3 21.6 -
Sharma and
Anil, 2003
Cefotaxime Bufalo calves - 10
SC
- - 14.3 40.5 2.83
Sharma and
Anil., 2006
Ceftazidime
Febrile
buffalo
calves - 10
IV
- - 217.3 952.9 -
Sharma and
Shah, 2012
82
Cefotaxime
Buffalo
calves
febrile)) - 10
IV
- - 15.8 - -
Sharma et al.,
2006
Cephradine
Healthy adult
male 250 - PO 11.49 0.76 - 14.23 17.81
Shoaib et al.,
2008
Cefixime
Healthy
volunteers 200 - Oral Tablet 3 3.5 22 - -
Shu-Ying et
al., 2009
Cefixime - 200 - Oral capsule 2.8 4.4 22.6 - -
Shu-Ying et
al., 2009
(Cis-isomer)
Cefprozil
Lactating
females - - - 14.8 2 54.8 - 3.38
Shyu et al.,
1992
(Trans-
isomer)
Cefprozil - - - - 1.9 2 6.2 - 3.41
Shyu et al.,
1992
Ceftriaxone Calves - 10
IV
- - - - 94
Soback and
Ziv, 1988
Ceftriaxone Calves - 10 IM - - - - 137.6
Soback and
Ziv, 1988
Ceftazidime Male 1000 -
IV
- - 153.2 - -
Sommers et
al., 1983
Ceftazidime Female 1000 -
IV
- - 179.8 - -
Sommers et
al., 1983
83
Ceftazidime Male 1000 - IM - - 120.5 - -
Sommers et
al., 1983
Ceftazidime Female 1000 - IM - - 169.4 - -
Sommers et
al., 1983
Cefoperazone Healthy adult 1000 -
IV
61.9 1.9 - - -
Sootornpas et
al., 2011
Ceftazidime Juvenile
loggerhead
sea turtles -
20
IV
- - 1567 49860 31.7
Stamper et
al., 1999
Ceftazidime
- -
20
IM - - 1393 44169 31.7
Stamper et
al., 1999
Cefixime
Healthy male
volunteers 400 - - 3.7 6.7 - - -
Stone et al.,
1988
Ceftriaxone
Sheep - 10
IV
- - 43 - -
Swati et al.,
2010
Ceftriaxone
Sheep - 10 IM 16 - 48 - -
Swati et al.,
2010
Ceftifur Healthy pigs - -
IV
12.9 0.5 168 4535 27
Tantituvanont
et al., 2009
Ceftriaxone
Goat - 20
IV
- - 78 - -
Tiwari et al.,
2009
Ceftriaxone Goat - 20 IM 22 - 67 - - Tiwari et al.,
84
2009
Ceftriaxone
Transplant
recepients 2000 -
IV
318 - - - 29.9
Toth et al.,
1991
Ceftriaxone
Normal
subjects 2000 -
IV
257 - - - -
Toth et al.,
1991
Ceftizoxime
Female and
male subjects 2000 -
IV
114.37 - 192.52 - -
Valle and
Marc, 1991
Ceftizoxime - 2000 -
IV
125.86 - 141.93 - -
Valle and
Marc, 1991
Cefixime
Patients of T-
tube drainage - - - 2.3 5.1 20 - -
Westphal et
al., 1992
Cefixime
Healthy
volunteers 200 - Oral Tablet 3.0 3.5 26.8 - -
Yan et al.,
2003
Cefixime
Healthy
volunteers 200 - Granules 3.1 3.2 28.5 - -
Yan et al.,
2003
Cefixime
Fasting
subject 200 - - 2.7 3.7 25.4 - -
Yaoguo et
al., 1994
Cefixime
Non-Fasting
subjects 200 - - 1.7 3.3 13.9 - -
Yaoguo et
al., 1994
Cefixime
Patients with
RTIs (M&F) 200 - - 2.64 4 21.24 - -
Yi et al.,
1995
Cefixime Healthy male 200 - Oral capsule 2.33 4.5 15.9 - - Yu-fei et al.,
85
2004
Cefixime - 200 - Oral capsule 2.28 4.28 16 - -
Yu-fei et al.,
2004
Cefixime Healthy male 400 - Oral Tablet 4.75 - 45 - -
Zakeri et al.,
2008
Cefixime - - - Oral Tablet 4.73 - 45.2 - -
Zakeri et al.,
2008
Cefuroxime
sodium
Beagle
dogs - 40
IV
84.2 0.54 121.5 187.2 1.54
Zhao et al.,
2012
Cefuroxime
lysine - - -
IV
92.46 0.5 130.9 181.1 1.39
Zhao et al.,
2012
Cefuroxime
lysine Rats - 67.5
IV
- - 45.29 16.84 0.37
Zhao et al.,
2012b
Cefuroxime
lysine Rats - 67.5 IP - - 58.12 55.33 0.93
Zhao et al.,
2012b
Cefuroxime
lysine Rats - 67.5 IM - - 55.31 36.17 0.65
Zhao et al.,
2012b
Ceftriaxone
Males and
females 1000 - IM 130.6 1.4 1493 - -
Zhou et al.,
1985
Ceftriaxone - 1000 -
IV
- - 1507 - -
Zhou et al.,
1985
86
RTI = Lower Respiratory Tract Infections PO = Per Oral OD = Once Daily
IV = Intra Venous IM = Intra Muscular SC = Sub Cutaneous
130
2.3.4 Urinary excretion and renal clearance:
The concept of renal clearance has proved useful in estimating kidney function. The
clearance rate of any substance is the volume of plasma which contains the amount of
substance excreted through urine in a unit time. The term clearance can be applied for any
substance in the plasma which appears in the urine by whatever process it reaches the urine,
filtration, secretion or excretion or a combination of these. Clearance rates of suitable
substance reveal the glomerular filtration rate. Creatinine is completely filtered at the
glomerulus and is not reabsorbed in the tubules and the endogenous creatinine renal clearance
is very widely used in clinical practice to give an estimate of GFR (Ahmad, 1983).
2.3.5 Bioequivalence:
Bioequivalence may be defined as a bioavailability study comparing two or more
different dosage form or different formulations of a dosage form of the same parent drug,
when comparing different dosage forms intravenous injection or oral solution is taken as
acceptable standard. Bioequivalence tells us that a drugs in given two or more similar dosage
forms reach the general/blood circulation at same relative rate and to same relative extent, in
which the profiles of plasma level of the drug are achieved using the two dosage forms are
super imposable (Remington, 1975). Drug product of a chemical equivalents whether
different dosage forms or different formulation of a dosage form are assumed bioequivalent if
the difference between the bioavailability of these products is not significant i.e. not more
than ±20%. Some pharmaceutical equivalents may be equivalent in regarding their absorption
rate and considered bioequivalent. Such differences in absorption rate are intentional and also
reflected in its labels. This is due to the fact, that when in chronic diseases, the attainment of
effective body drug concentration is not essential or when it is considered medically
insignificant for the particular product (Parveen, 1982).
The efficacy of a single dose of a drug is a function of both the rate and extent of
absorption of drug, so, to assure the bioequivalence of two dosage forms of same
formulation, not only the drug amount absorbed from each is important, the absorption rate of
drug from each drug product must also be comparable (Gibaldo, 1977), e.g., the drug may be
100% absorbed following oral administration and yet be ineffective due to a release rate that
is slow that the concentration in the blood at no time achieves the required level. Conversely,
the release may be too fast, giving the patient such a rapid result that undesirable side effects
are experienced.
131
Generally, bioequivalence should be shown for the drugs which are used in serious
illness, drugs which have steep dose response curves or serious undesirable effects and finally
those drugs which have poor water solubility or convert to water insoluble forms in the
gastrointestinal tract, making dosage form factor as possible rate limiting step in the
absorption process. Several recent studies have demonstrated bioequivalence of chemically
equivalent drug products (Barr et al., 1972; Chiou, 1972; Wagner et al., 1973).
Bioequivalence requirements are imposed by FDA for In-vivo and In-vitro testing of the
specified drug products.
2.3.6 Studying pharmacokinetics of a drug:
Prior to bioavailability or bioequivalence study, important task for the investigator is
to make decision about the nature and type of experimental design, dose system, sampling
compartment, extent of estimation and method of estimation. He has to select one way out of
different followings according to the need and facilities available:
Experimental design: - Complete crossover, Latin Square, Balanced incomplete block design.
Dose system: - Single dose, multiple dose.
Sampling compartment: - Blood level data, urinary excretion data.
Extent of estimation: - Parent drug, total drug (active and bio-transformed form of drug).
In comparing of bioavailability of two or more drug products, a complete crossover or
any other statistically sound experimental design is necessary to have a direct comparison of
the absorption of each drug product in the same individual and to estimate the biological
effect. A sufficient time interval between the administrations of two drug products is given to
an individual for avoiding carryover effects of the drugs (Parveen, 1982).
2.4 Factors effecting drug pharmacokinetics:
132
Most antibacterial drugs have a wide therapeutic margin; therefore individualized dosage
is not essential. However, the dose must be determined relative to age, absorptive surface
area, body composition and maturation of body systems.
Antibiotics have a great role in treatment of many human and animal's infections. For
treatment of microbial infections, an effective concentration of antibacterial agent should
reach at site of infection and it should be maintained there for an appropriate time. This
achieved concentration is dependent on systemic availability of drugs. This bioavailability of
drug depends upon itsdosage form, route of administration, dosing rate and frequency, ability
to reach at the site of infection. Physicochemical characteristics of the drug also affect the
pharmacokinetic characteristics like drug concentration, rate and extent of absorption,
distribution pattern and mechanism of drug elimination. Susceptibility of microorganisms to
the antibiotics is also an important clinical aspect for drug's efficacy. Thus an effective
antibiotic therapy depends on the bacterial susceptibility, dosing rate and pharmacokinetic
characteristics of the drugs.
Correlation within In-vitro and In-vivo Parameters:
In the field of biopharmaceutic, the study of the physical and pharmaceutical factors
influencing the bioavailability of a drug from its different preparations has been very
interesting topics for many research workers (Aguiar et al., 1968).
2.4.1 Particle size, viscosity and surface area:
From intramuscular dosage forms of the drug, absorption may be affected by the
viscosity of suspension. The effect of the viscosity on the drug absorption was evaluated by
administration of suspensions, having same particle size and same formulation. In different
cases the effect of viscosity on the drug absorption could be negligible, as in the case of
chloramphenicol (Kitamori et al., 1976). By all possible manipulation in physical properties
of chloramphenicol to yield better drug absorption, the reduction of particle size is the most
widely exploited. Increased absorption due to reduction of particle size (Renihold, 1945) is
the result of increased dissolution, which is in turn the result of a large surface area being
exposed to the fluids in the gastrointestinal tract or to other sites of administration. The
breakdown of a 3 mm3 into 1 mm3 particles results into a 300% increased in the exposed
surface area.
2.4.2 Role of drug solubility:
133
Cefixime is recommended as first line antibiotic in community-acquired URTI
(Hedrick, 2010) however; in some publications cefixime has been demonstrated as drug
withpoor efficacy (Dreshaj et al., 2011). Therapeutic efficacy of an oral product depends on
its absorption in GIT. However for absorption, the drug is needed to be solubilized. Solubility
has a crucial role for bioavailability of oral drug, particularly for the drugs having low
gastrointestinal solubility and having low permeability . Bioavailability can be enhanced by
improvement of solubility of a drug (Suchetha et al., 2010). Cefixime is not soluble in acidic
medium. After its oraladministration; it is slowly and incompletely absorbedfrom the
gastrointestinal tract, which results into poorbioavailability (Ali and Omair, 2012). A drug's
therapeutic actions depend upon delivery of the medicaments from its dosage form to the site
of action at a rate and amount sufficient to produce thedesired pharmacological response.
Oral ingestion is commonly employed as the most convenient route of drugdelivery due to
different reasons such as its ease of administration, cost-effectiveness, least sterility
constraints, high patientcompliance and flexibility in the design of dosage form. Poor
bioavailability is the major challenge with oral dosage forms. Different factors which may
affect oral bioavailabilityinclude; aqueous solubility, dissolution rate, drug permeability, first-
pass metabolismand pre-systemic metabolism. Low permeability and poor solubility are the
most frequent causesof low oral bioavailability (Bajaj et al., 2011). Cefixime has low
solubility and reasonable permeability. This study was conducted to evaluate
whetherimprovement in solubility of cefixime oral Tabletenhances its efficacy in upper
respiratory tract infection. In this study, both the study drugs (improved form and
conventional one) significantly reducesymptoms of URTI on day 5 from baseline. Reductions
inclinical symptoms were significantly more in patientstreated with improved formulation of
cefixime thanconventional cefixime Tablet. This result suggested thatimproved formulation
of cefixime shows fasterimprovement in signs and symptoms of URTI thanconventional
cefixime Tablet. Greater efficacy ofimproved formulation of cefixime may be due to
higherbioavailability of cefixime (Nerurkar et al., 2013).
2.4.3 Influence of genetic variation on drug's pharmacokinetics:
Many developing countries, such as Pakistan, import raw and finished drugs.
Preclinical and clinical trials for drug development in drug exporter countries are done. In
certain cases the environmental conditions and genetic makeup of animals in importing
134
countries are different than in exporting countries. In several studies the optimal dosage,
pharmacokinetic behavior, urinary excretion and renal clearance of the imported drugs under
investigation were different under the indigenous condition than the values mentioned on the
product inserts or in the manufacture's literature. The term "geonetics" describes the influence
of environment on the genetics and it is manifested by physiological and biochemical
characteristics / parameters which ultimately have an effect on bio-disposition and fate of
drugs in the body of a population (Nawaz, 1982; Nawaz and Shah, 1985; Nawaz, 1994;
Muhammad, 1997). These geonetical influences has been reported for pH of blood and urine,
plasma proteins, metabolism of drugs and renal functions in cows, buffaloes, goats and sheep
(Nawaz et al., 1988). It may be concluded from such studies that geonetical conditions may
influence the physiological and biochemical parameters and thus ultimately fate and
disposition kinetics are affected resulting in changed response towards the drug. Several
studies in animals show that bio-disposition of certain drugs, i.e. sulfonamides; under
indigenous condition is different from pharmacokinetics recorded elsewhere (Nawaz et al.,
1989).
So the optimal drug dosage regimen is based on pharmacokinetic profile in species
and also the environment where which drug is being employed clinically.
2.4.4 Dehydration:
The dehydration occurs in body due to any of the following reasons:-
Environmental water deprivation.
Excessive sweating in warm climatic and during exercise.
In some diseases like polyuria and diarrhea, etc.
A number of physiologic and biochemical changes have been attributed to temporary
dehydration which can significantly modify the disposition of drugs in the body. When
electrolyte and water changes in tropical marine sheep, exposed to dehydration in summer
was observed (Macfarlane, 1961), it was found that after an initial increase, the plasma and
extracellular volume decreased as much as 45% while concentrations of hemoglobin and
plasma proteins increased by 60%. In plasma K and Na concentrations were increased less
than that of Hb.
In last 10 years, the electrolyte and urea concentrations during dehydration, the renal
regulation of acid-base equilibrium, effect of mild dehydration in creatinine clearance rate,
135
effects of acute water restrictions on plasma proteins, effect of dehydration on systemic fluid
balance and subjective sensations where determined in different animals by many worker
(Rolls et al., 1980). It is evident from the findings of reported dehydration studies that during
such condition the kinetic of a drug may significantly be changed resulting in altered efficacy
and toxicity, which might necessitate a new basis of drug selection and dosage regimen
modification.
2.4.5 Influence of age on cefixime pharmacokinetics:
Mean maximum plasma drug concentration and the area under the time and the
plasma drug value curve were increased by 26% and 20%, respectively, in elder subjects as
compare to young subjects after oral administration of 400 mg per day of cefixime for 5 days
(Silber et al., 1988). However, dose adjustment according to age alone should not be
necessary (Brogden and Campoli-Richards, 1989).
2.4.5.1 Influence of age on drug absorption:
Drug absorption is characterized by passage of the drug from its site of administration
into the blood circulation stream. Therefore, developmental changes during the first few days,
months, or years of life influence both the rate and extent of oral drug absorption in pediatric
patients. Stomach acidity is decreased in pediatric patients by frequent intake of milk. When
pH environment of stomach is high, the drugs having nature of weak acids are slowl y
absorbed than the weak basic drugs. Therefore, since children tend to have decreased gastric
acidity, weak acidic drugs are absorbed more slowly and the drugs that are weak bases are
absorbed faster in pediatric patients than in adults. Bioavailability of some weakly basic
drugs such as ampicillin was found to be increased in neonates as compared to elder children
(Silverio and Poole, 1973) whereas bioavailability of weakly acid drugs such as
acetaminophen (Levy et al., 1975) and riboflavin (Jusko et al., 1976) was decreased in
neonates as compared to elder children.
2.4.5.2 Influence of age on drug distribution:
Drug distribution is a process when drug leaves the blood stream reversibly and enters
the cells of tissues and/or extracellular fluid. Distribution of drugs in the body is related to
body composition. Neonates have a much high proportion of body mass in the form of water
than elder children or adults. Total body water (TBW) in infants is about 75% of body mass
whereas it’s about 85% of body mass in small premature infants. The level of TBW gradually
136
decreases with age; adult value (55% TBW) is attained by 12 years of age (Cheek et al.,
l966).
Volumes of intracellular water (ICW) and extracellular water (ECW) are also higher
in children, infants and neonates as compared to adults. Therefore, volume of drug
distribution, which is parallel to body water contents, is higher for children than adults. For
example, aminoglycosides are water soluble antibiotics and distributed initially in a volume
approximating extra-cellular fluid volume (0.2 to 0.3 L/Kg in adults as compared to 0.5 to l.2
L/Kg for neonates, infants and children). Since half-life of drugs (which is related to the time
required to achieve a desired steady state serum concentration) is influenced by volume of
distribution, it’s an important consideration in designing dosage regimen. Patients with cystic
fibrosis have an increased intravascular fluid volume as a result of cor-pulmonale; therefore
volume of distribution of both gentamicin and tobramycin is increased in those patients as
compared to normal control subjects (Kearns et al., 1982; Kelly et al., 1982). Similarly, total
body water decreases and body fat increases with age (Boreus, 1982). Therefore, lipid-
soluble drugs, such as diazepam, are less distributed in infants and children as compared to
adults, due to lack of adipose tissue and high extracellular water content in young children.
Permeability of cell membranes is greater in immature infants; therefore drug entry
into some compartments is enhanced. Brain-plasma ratios of anticonvulsant drugs are higher
in infants and children as compared to adults (Assael, 1982; Comford et al., 1983). The
important factor of influencing drug distribution is the extent of drug protein binding.
Albumin concentration directly increases with gestational age. Neonate serum contains
approximately 80% protein (Boreus, 1982). Similarly, binding affinity to albumin for many
drugs appears lower in neonates than in adults. Albumin binding of salicylate and propranolol
is low in infants as compared to adults (Morselli, 1976). This low affinity of binding may be
due to a competition for binding with endogenous substances, such as bilirubin and fatty
acids, which have higher levels in neonates as compared to adults (Broderson et al., 1983).
2.4.5.3 Influence of age on drug metabolism:
Drug metabolism is the process by which drug is chemically converted in the body to
metabolites, which may have varying degrees of activity when compared to the parent drug.
This conversion is usually enzymatic but occasionally non-enzymatic. However, drug
metabolism may change with age. The enzymatic system, which is responsible for drug
metabolism is immature (less active) at birth and its capacity increases with advancing age
137
(Juchau et al., 1980; Thurman and Kaufman, 1980). This low activity may be due to low
levels of hepatic uptake, low concentrations of intracellular carrier or low levels of bile
production (Morselli, 1976; Morselli et al., 1980). However, it was found that the activity of
metabolic enzymes in neonates, infants and children is about 20 to 70% of adults, revealing
that actual enzyme activity does increase with age (Boreus, 1982).
Conjugation activity of endogenous substances and drugs is low at birth; increases to
reach adult levels (in children) by three years of age (Morselli et al., 1980; Assael, 1982).
Drugs which are mainly excreted through bile may become toxic in neonates and infants due
to low activity of the enzymatic system responsible for their detoxification and elimination.
2.4.5.4 Influence of age on drug excretion:
Drug excretion is the irreversible removal of drug (unchanged or as its metabolites)
from the body by various routes such as urine, bile (feces), respiration, milk, skin and saliva.
The most important excretory organ is the kidney which excretes non-volatile substances.
Blood flow, glomerular filtration rate, ability to concentration and acidity and tubular
function (including re-absorption and secretion) are lower in children and infants as compare
to adults. Thus, renal function in infants and children is lower as compared to adults. It was
found that the rate of glomerular filtration is low in neonates then increases gradually to adult
values by three years of age (Barnes and Goodwin, 1983). When gentamicin was applied in
premature infants, its serum concentration was high because its elimination rate was low
(Szefler et al., 1980). The excretion rate of penicillin in neonates was lower than that of
adults, because it is mainly secreted through renal tubules (Morselli, 1976). Passive tubular
re-absorption may be low in infants and neonates (Morselli et al., 1980) and their relatively
low urinary pH may also influence the rate and extent of absorption of drug. It was found that
the renal clearance of digoxin parallels the maturation of kidney function (Morselli et al.,
1980).
2.4.6 Influence of liver dysfunction on drug pharmacokinetics:
Liver is an important organ of drug metabolism. Plasma clearance of many drugs
having elimination by biliary excretion and / or biotransformation may be reduced by liver
dysfunction but it can affect plasma protein binding also which in turn influences the
distribution and elimination processes. Therefore, the pharmacokinetics of drugs being used
138
to treat typhoid fever may be affected because of transient liver dysfunction due to typhoid
fever, so, in turn pharmacological or toxic effects of these drugs may also be affected.
2.4.6.1 Influence of liver dysfunction on drug absorption:
After absorption of an oral drug, it passes through the portal vein into the liver before
reaching systemic circulation, resulting in first-pass effect. The fraction of absorbed drug,
which escapes this pre-systemic elimination, is related to hepatic excretion rate and the
fraction of splanchnic blood flow passing through the functional liver. Thus, when the liver is
functioning efficiently, only a small fraction of drug reaches general circulation, whereas, in
drugs that are poorly eliminated through the liver, a large fraction reaches general circulation.
Studies have clearly demonstrated that, in cirrhotic patients, the bioavailability of an oral
drug may be increased. Examples of this increased bioavailability are lidocaine (Huet and
Villeneuve, 1983), penzocin (Neal et al., 1979), labetalol (Homeida et al., 1978) and
propranolol (Wood et al., 1978). On the other hand, liver blood flow (that carries drugs into
the circulatory system) may also affect the bioavailability of drugs. Total liver blood flow in
chronic liver disease is decreased (Branch and Shand, 1976) while it is unchanged in acute
viral hepatitis (Preisig et al., 1966). Therefore, an alteration in hepatic hemodynamic, which
may occur in liver disease, may cause changes in pharmacokinetics of drugs.
2.4.6.2 Influence of liver dysfunction on drug distribution:
Liver is the major organ for the synthesis of plasma proteins such as α1 -acid
glycoprotein and albumin onto which drugs may bind. Therefore, this binding may alter in
liver disease (which is associated with decreased concentrations of plasma proteins) resulting
in increased free drug concentration, which may increase the volume of distribution of drug.
Narang, (1985) reported that, there is significant correlation between antipyrine half-life and
serum albumin concentration. In cirrhotic patients as well as patients with acute viral
hepatitis, the binding rate of many drugs is lower than that of healthy subjects. This was
found with stavudine (Schaad et al., 1997), meropenem (Thyrum et al., 1997), lorazepam
(Kraus et al., 1978), propranolol (Branch and Shand, 1976; Branch et al., 1976; Wood et al.,
1978), diazcpam (Klotz et al., 1975; Thiessen et al., 1976), quinidine (Affrime and
Reidenberg, 1975) and phenytoin (Blaschke et al., 1975).
In addition, during liver disease, the metabolism of some endogenous substances such
as urea and bilirubin is inhibited, resulting in an increase in their blood levels. These
139
substances may compete with drugs for their binding sites (Cortes et al., 1990). However,
volume of distribution of some drugs such as tolbutamide does not change in acute viral
hepatitis because the extent of drug binding to the tissues is increased along with changes in
plasma proteins (Lewis and Jusko, 1975; Wood et al., 1978).
2.4.6.3 Influence of liver dysfunction on drug metabolism and excretion:
Biomedical and physiological problems/disturbances caused by hepatic diseases may
enhance the drug's toxicity. During early stages of the disease, metabolism of many drugs is
faster than that in normal subjects because multiple doses of ethanol induces the cytochrome
P-450 dependent monooxygenases (Vesell et al., 197l). However, with time, functional
hepatocytes convert into fibrous bands, incapable of metabolizing drugs. Such that
cytochrome P-450 isozyme and conjugation pathways may be decreased by this condition
(Paintaud et al., 1996).
Many investigators have demonstrated impaired clearance of antipyrine (Narang,
1985), theophylline (Staib et al., 1980) and clofibrate (Gugler et al., 1979) in patients of liver
cirrhosis. In contrast, clearance of drugs, such as lorazepam (Kraus et al., 1978) and
oxazepam (Shuil et al., 1976) is not affected by liver cirrhosis. It is apparent that in addition
to considerable patient variability, all drugs are not equally affected. There is selective
impairment of different routes of metabolism due to the effects of varying degrees of liver
dysfunction.
2.4.7 Influence of malnutrition on drug pharmacokinetics:
Approximately 80% of pediatric population of the world has been estimated living in
countries having limited resource and 43% of all these children have been found
malnourished (Merry et al., 1998). Malnutrition is a complex condition in which many patho-
physiological changes occur simultaneously. These changes may affect drug
pharmacokinetics. Suskind (1975), Walker (1987) and Gupta et al. (1970) reported that
malnutrition results in a decreased surface area due to impaired cell proliferation, alterations
in the intestinal flora, hypochlorhydria, delayed gastrointestinal emptying time and increased
or decreased intestinal transit time.
140
Severely malnourished individuals also exhibit decreased drug oxidation, conjugation
and protein binding rates, reduced glomerular filtration rates, potentially increasing
concentrations of the parent drug or its active metabolites (Merry et al., 1998).
Krishnaswamy, (1978) reported that the liver is very sensitive to lack of dietary proteins.
Basal metabolic rate is reduced with impaired synthesis of protein (albumin) in liver during
malnutrition.
The Kidney also appears to be susceptible to changes in dietary intake in children.
Reduction in glomerular filtration and renal plasma flow are documented in malnourished
children (Alleyne, 1967). However, as a consequence of various physio-pathological
variations, there may be a wide range of changes in drug pharmacokinetics as indicated
earlier.
2.4.7.1 Influence of malnutrition on drug absorption:
The rate of absorption of oral drugs is influenced directly by changes in the
gastrointestinal tract such as pH, surface area, blood flow, flora and gut wall metabolism.
Low plasma concentrations of some drugs due to impaired absorption in malnourished
children were reported for drugs such as chloramphenicol (Eriksson et al., 1983) and
chloroquine (Walker et al., 1987). In addition, the absorption rate of tetracyclines, rifampicin
and anticonvulsants are documented to be low in malnourished adults (Raghuram and
Krishnaswarny, 1981; Polasa et al., 1984; Barro et al., 1985).
2.4.7.2 Influence of malnutrition on drug protein binding:
Malnutrition significantly alters plasma and tissue proteins synthesis. A significant
reduction in binding of several drugs has been reported in malnutrition for both adults and
children. Protein binding of quinine (Pussard et al., 1999), penicillin (Bolme et al., 1995),
antipyrine (Tranvouez et al., 1985), acetaminophen (Buchanan et al., l980b), sulfadiazine
(Mehta, 1990), tetracycline (Krishnaswamy, 1987), doxycycline, rifampicin and
phenylbutazon (Krishriaswamy et al., 1981) and chloramphenicol (Eriksson et al., 1983;
Mehta, 1983) was decreased. Volume of distribution of gentamicin, cefoxitin, paracetamol
and antipyrine dropped in malnourished children as compared to healthy children (Raghuram
and Krishnaswamy, 1981).
2.4.7.3 Influence of malnutrition on drug metabolism and excretion:
141
Many studies have reported the effects of the malnutrition on elimination of drugs.
Serum concentration and elimination half-life were reported to be increased whereas volume
of distribution and clearance were decreased for many drugs such as antipyrine (Buchanan et
al., 1980a), theophylline (Eriksson et al., 1983), acetanilide (Buchanan et al., l980b),
phenobarbitone (Syed et al., 1986), chloramphenicol (Eriksson et al., 1983), paracetamol
(Mehta et al., 1985), salicylate (Buchanan et al., l980a) and sulphadiazine (Mehta., 1990). In
addition, tissue binding of drugs changed in malnourished children (Krishnaswamy, 1987).
There are also indications that protein depletion can impair plasma clearance of bilirubin,
resulting in increased levels in blood, which may compete with some drugs for their binding
sites (Flesher, 1976; Gollan et al., 1976). It was reported that serum levels of α1-acid
glycoprotein was increased in malnourished subjects and was associated with increase in the
binding rate of propranolol (Jagadesan and Krishnaswamy, 1985).
2.4.8 Influence of fever on drug pharmacokinetics:
Fever is a complex physiologic response characterized clinically by a rise in body
temperature above the normal range. However, the role of fever on drug pharmacokinetics
(absorption, distribution, metabolism and excretion) has received little attention in the clinical
literature.
2.4.8.1 Influence of fever on drug absorption:
During fever, the absorption of a drug from the gastrointestinal tract may be altered
due to changes in its physiological function and systemic circulation. Fever is accompanied
by several physiological alterations that may affect drug absorption. Gastric secretion
decreases in febrile patients (Chang, 1933) such that temperature of the body does correlate
inversely with histamine-stimulated output of peptic acid. Similar findings in dogs were
reported (Blickenstaff and Grossman, l950). Emptying of the gastrointestinal tract also slows
in febrile illnesses (Beresford et al., 197 l), which may affect the rate of absorption.
During fever tachycardia is very common and the associated increase in the cardiac
output make a contribution to an increased blood flow to gastrointestinal tract (GIT).
Increased blood flow to GIT should speed up the rate of absorption of drugs that are
administered orally. But surprisingly, profound decreased absorption of pre-labeled ferrous
ascorbate was observed in children of febrile illness or a febrile response to diphtheria-
pertussis-tetanus immunization (Beresford et al., l971).
142
Similar findings were reported in the rats' injected intra-peritoneal with endotoxin
derived from E.coli (Cortell and Conral, 1976).
Additional investigations related to the influence of fever on drug absorption
including that of Van-Miert and Parra, (1970) who reported that during fever the absorption
of sulfonamide was enhanced in four of six animals studied. These findings were out of
expectation because previous studies on mono-gastric animals demonstrated the inhibition of
both the stomach secretions and the time of gastric emptying by E. coli endotoxins (Leenen
and Van Miert, 1969; Van-Miert and Parra, 1970).
In another study the effects of endotoxin induced fever was examined on the
pharmacokinetic of gentamicin in rabbits. In this research experimental model, fever
appeared to increase gentamicin absorption from intramuscular sites of injection, possibly
due to increased blood flow to the absorption sites under febrile conditions (Halkin et al.,
1981). Significantly increased absorption of oral trimethoprim was observed after the
treatment with a peptidoglycan pyrogen derived from Streptococcus pyrogenes (Lavicky et
al., 1986). Similar findings were observed in studies of rifampicin pharmacokinetics in calves
and rabbits (Lavicky et al., 1986).
2.4.8.2 Influence of fever on distribution of drug:
Many drugs in different studies have shown the inverse relationship between protein
binding and body temperature (Ballard, 1974). With highly albumin-bound drugs, both the
bound fraction and binding constant decreased with increase in body temperature. Because
unbound drug molecules diffuse freely from intravascular compartment into tissues, fever
would be expected to potentials penetration of drugs with normally high binding constants.
Serum concentration of gentamicin was decreased in dogs with fever induced/caused
by either endotoxin or etiocholanolone (Pennington et al., 1975). This may result from a
potentiating effect of fever on tissue penetration by gentamicin. Other parameters like
serum/plasma t1/2 and ClR of gentamicin were not significantly altered during fever. Several
other investigators reported an increase in volume of distribution of ciprofloxacin and
cefazolin (Beovic et al., 1999a,b), ceftriaxone (Acharya et al., 1994) and gentamicin
(Pennington et al., 1975; Halkin et al., 1981). These studies indicate that fever might enhance
drugs diffusion into peripheral compartments. However, several studies also suggested that,
this phenomenon is not universal.
143
It was observed in ewes that a fraction of gentamicin residing in the central
compartment was increased as a response of fever induced by endotoxin while the gentamicin
amount was decreased in the tissues or peripheral compartments (Wilson et al., 1984).
According to another study fever causes significant increase in level of rifampin in blood and
tissues. In later experiments, fever was observed to cause in the delay of transport of rifampin
from blood or circulation into the diseased parts or organs (Leszczynska, 1979).
The disposition kinetics or pharmacokinetics of an anti-protozoan drug, imidocarb, in
febrile goats and dogs (induced by different pyrogens) was studied. It was noted that fever
significantly altered the apparent volume of distribution and systemic clearance of drugs,
which varied according to the agents used, inducing the febrile reaction (Abdullah and
Baggot, 1984).
2.4.8.3 Effect of fever on the drug biotransformation and excretion:
As indicated earlier increased cardiac output and subsequent increased blood flow to
the liver and kidney might lead one to expect an accelerated biotransformation and
elimination of drugs in the febrile subjects. However, it will be difficult to reconcile this
conclusion with the reports that bacterial endotoxin inhibits various liver functions e.g.
glucocorticoid-mediated induction of tryptophan oxygenase and phosphoenol pyurvate
carboxykinase, michrosomal cytochrome P450 and related drug metabolizing enzymes
(Bissell and Hammaker, 1976; Gorodischer et al., 1976).
Similarly, recent data suggests that pyrogenic cytokines, such as interleukins (IL)
especially IL-1 and IL-6 and interferons (IF) especially IF-alpha and T-gamma (the principle
endogenous mediators of the febrile response) are also probable mediators of the inhibitory
effects of endotoxins on hepatic function (Okuno et al., 1990). These data show that fever
inhibits rather than to facilitate the metabolism of drugs.
Few studies demonstrated the effect of pyrexia on drug biotransformation and/or
elimination (Pennington et al., 1975; Leszczynska, 1979; Demotes-Mainard et al., 1988).
These studies suggest a complex relationship exist between drug metabolism or elimination
and fever; this may be a reflection of the opposing behavior of fever on hepatic metabolic
function and hepatic blood flow.
The effects of pyrogen induced pyrexia was examined on metabolism of salicylamide
in human volunteers; it was found that fever have an association with a decreased drug's
144
transformation into its major metabolite "salicylamid glucuronide" and simultaneously
increased drug's conversion into other minor metabolites (Song et al., 1972). Therefore, in
this study as well as in two others (Van-Miert and Parra, 1970), fever was found to induce a
complex alteration in the drug biotransformation which is characterized by certain
accelerated pathways and concomitant retardation of some others.
In addition, two studies on pharmacokinetics of gentamicin (Pennington et al., 1975)
and two studies of thiophylline pharmacokinetics (Prince et al., 1989) found no effects of
fever on drugs metabolism. It was reported that fever (endotoxin induced) caused inhibited
elimination of rifampin in the rabbits (Leszczynska, 1979). Similar results were found in
studies of quinine metabolism in malarial patients' treatment (Trenholme et al., 1976), as in
studies of antipyrine metabolism in children (Forsyth et al., 1982). Also, metabolism of
phyllin, metronidazole and antipyrine were significantly decreased in malaria endotoxine-
treated rats (Kokwaro et al., 1993a,b,c).
Malarial infection caused a decrease in clearance of metronidazole and caffeine but
had no effect on antipyrine and phylline metabolism. Based on these observations, the
authors concluded that both malarial infections and fever influences the low capacity
components and the high affinity of the two-enzyme metabolism model, with little influence
on the high capacity components and low affinity.
In keeping with this theory, it was suggested that although malaria and endotoxin-
induced fever may influence P-450 dependent drug metabolism, such effects appear to be
isozyme selective (Kokwaro et al., 1993a). A similar hypothesis was proposed to explain the
elevated nitrendipine plasma level compared with unchanged bisoprolol in patients with acute
febrile illness (Soons et al., l992).
Thus, in conclusion it can be stated that fever has a complex relationship existing
between the pyrexia and drug biotransformation or elimination. This may be due to opposing
effect of fever on hepatic blood flow and metabolic functions of liver.
2.4.9 Role of gender in pharmacology of a drug:
2.4.9.1 Pharmacodynamic and pharmacokinetic:
Study of drug mechanism of action, biochemical and physiological effects of drug on
body, relationship between rate and extent of pharmacologic response and drug concentration
145
is called Pharmacodynamic. So, in given concentration of blood, a drug may cause variable
response (like differences in safety/effectiveness).
2.4.9.1.1 Role of gender in disease occurrence:
Physiologic differences existing between women and men play a role in prevalence
and outcomes of the disease. For example, men are less likely to develop cataracts, thyroid
dysfunction, migraine, rheumatoid arthritis, depression, irritable bowel syndrome, hepatitis
and multiple sclerosis than women and women are less likely to develop myocardial
infarction, but within a year after MI women are more likely to be expired. On the other hand,
women have more life expectancy than men inspite of having increased susceptibility of
many diseases. Gender differences also have implications on pharmacodynamic and
pharmacokinetic of the drugs (Whitley and Lindsey, 2009).
2.4.9.1.2 Adverse effects in gender:
In the target population, knowledge of drug pharmacodynamic and pharmacokinetics
is needed for development of dosage regimens. Drug side effects are less frequent in men as
compared to women; this may be due to 2 possibilities, (1) Normalized dose taken by men is
lower than women. (2) Physiological and anatomical differences in gender may have effect
on drug pharmacokinetics. Differences in systemic clearance and distribution volume can
explain most of these changes and pre-systemic clearance may have a role in these
dissimilarities. In general men have lower drugs plasma levels, but after normalization of data
by the body weight, these differences usually are abolished or reduced, because both the
systemic clearance and distribution volume are affected by it. However in some cases these
differences persist (Carrasco and Francisco, 2011).
2.4.9.1.3 Variables effecting prescription:
Pharmacological research has greatly strengthened our understanding of different
variables affecting the drug prescription. Gender is of increasingly recognized significance
among these variables. In the United States, annually up to 7000 deaths and 5% of all hospital
admissions are because of adverse drug reactions (Khon, 2000). Identification of factors that
may pre-dispose to adverse drug reactions is important in risk management.
2.4.9.1.4 Known risk factors for adverse drug reactions:
146
Known risk factors for adverse drug reactions are poly-pharmacy, liver and renal
disease, increasing age and female gender. Why female patients have this increased risk, it is
not clear, but this is due to gender related differences in pharmacodynamics,
pharmacokinetics, hormonal and immunological factors and also due to differences in the use
of drugs by men as compared to women (Carrasco and Francisco, 2011).
As compared to male patients, female has shown 1.5 to 1.7 times higher risk of having
ADRs (adverse drug reactions) [Kando et al., 1995]. Risks are higher by women than by men
and by people of color than by white people (Finucane et al., 2000).
2.4.9.1.5 Physiological and molecular factors changing drug disposition:
Sex-related differences in pharmacokinetics have been considered as an important
determinant for effectiveness (clinical) of drug therapy. The mechanistic factors resulting in
sex-specific pharmacokinetics can be divided into physiological and molecular factors.
Molecular factors involving in disposition of drug include metabolizing enzymes for drug and
transporters of drug (Meibohm et al., 2002).
Physiological factors causing sex-specific pharmacokinetics include the higher body
fat percentage, lower organ size and bodyweight, lower GFR (glomerular filtration rate),
slower gastrointestinal motility, different gastric motility and less enzymatic activity in
females as compared to males. Hence pharmacokinetics in women may be affected when it is
compared with males (Meibohm et al., 2002; Whitley and Lindsey, 2009).
2.4.9.2 Examples:
2.4.9.2.1 Women; more responsive to drugs:
Increased sensitivity and greater effectiveness of opioids,beta-blockers, typical
antipsychotics and SSRIs(selective serotonin reuptake inhibitors) are observed in females due
to pharmacodynamic differences and females are 50 to 75% more likely to develop ADRs
(adverse drug reactions) than males. Drugs causing prolong QT interval should be given
carefully in females, as females are more likely to develop torsades de pointes. Because of
high mortality rates females should take lower digoxin dosage than males (Whitley and
Lindsey, 2009).
2.4.9.2.2 Delayed gastric emptying:
147
It is needed in women to increase the time interval between eating (meals) and taking
those drugs, which are absorbed on empty stomach, because of slow stomach emptying in
women. Some drugs which are cleared through urine (e-g digoxin) may need an adjustment
of dosage in females, because of slower renal elimination in females (Whitley and Lindsey,
2009).
2.4.9.2.3 Kinetics and lower body weight:
Initial drug concentrations after a bolus dose or loading dose and maximum peak
concentrations (Cmax) are dependent on the volume of distribution (Vd). Average steady-state
concentrations (Css) are dependent on clearance (ClB). For the majority of drugs, Vd and ClB
are dependent on body weight; yet few drugs are dosed based on body weight. Generally,
males weigh more than females. Therefore, based on differences in body weight alone,
females often receive higher doses which results in higher concentration and drug exposure
than males, irrespective of other pharmacokinetic differences (Carrasco and Francisco, 2011).
2.4.9.2.4 Initial researches on role of gender on bioavailability:
In 1971, antipyrine was the first drug to be kept under gender analysis for
pharmacokinetic difference (Berg, 1999). Entire elimination of this medication is by
metabolism in liver and the study confirmed that antipyrine half life was shorter in women.
The next drug to be analyzed was acetaminophen; this drug clearance was slower in women
than in men.
2.4.9.2.5 More research is needed on gender difference:
When compared with age, genetics, social habits, disease and their likely interactions,
the relative role of gender on pharmacokinetics in the clinical setting is not known
completely. But it should be studied further and considered routinely (Schwartz, 2003).
In past times, there is relative deficiency of data to evaluate gender differences in side
effects and efficacy of drug, because of underrepresentation of females in clinical trials. Fear
of teratogenicity is a major reason for female underrepresentation and women were not
included in main studies involving the drug’s efficacy. The FDA includes more women in
clinical trials since 2000. Since then, growing information about the influence of gender in
the pharmacokinetics of drugs has been published (Carrasco and Francisco, 2011).
148
It is well known that some important physiological differences exists between male
and females, which may produce differences in the pharmacokinetics of drugs, so, all
processes involving in the drug absorption, distribution, metabolism and excretion may be
changed (Carrasco and Francisco, 2011).
2.4.9.3 Absorption:
2.4.9.3.1 Routes of administration:
Drug absorption is defined as the pass from the site of administration to the systemic
circulation. Depending on the route of administration, the drug has to cross several barriers
that may contribute to reduce the bioavailability.
Gender does not significantly affect the bioavailability and protein binding after
transdermal administration of drug and the sex does not significantly affect total drug
absorption, although rate of absorption may be slightly faster in men. After oral drug
administration, bioavailability of substrates for CYP3A may be lower in men than in women
(Schwartz, 2003).
2.4.9.3.2 Factors effecting oral medication:
When the drugs are given orally, it has clearly established that peptic acid secretion,
emptying time of stomach, gastrointestinal (GIT) blood flow; presystemic metabolism and
transporters activity influence the absorption of drugs. Although there is little information
concerning changes due to gender in such factors, it has been established that changes in the
bioavailability of several substances may occur (Walle et al., 1985; Timmer et al., 2000).
Difference in stomach pH, GIT (gastrointestinal) motility and enzymes activity affect
the drug absorption after oral administrations. Men secrete more gastric acid and have faster
gastrointestinal (GIT) transit times than women (Fletcher et al., 1994).
It has been reported that some hormones may change secretion of gastric acid.
Therefore stomach pH and additionally, a slower emptying time of stomach is present in
females (Gandhi et al., 2004). Such changes results in significant delay of the onset of
effectiveness of enteric-coated dosage forms and drug solubility and dissolution rate may be
modified (Donovan, 2005).
149
However, contradictory results have been published, since there is evidence indicating
that no change in the pharmacokinetic parameters is observed in several studies. As it can be
seen, it is not possible to predict that in which cases differences among men and women, in
the absorption of enteric coated formulations will be present, since several factors may
contribute to the possible gender differences and it is a quite difficult to establish if
differences are due to these factors.
Other factor that may give some contribution to sex related differences in drug PK
(pharmacokinetics) is the gastrointestinal blood flow (Fletcher et al., 1994). It has been
described that usually women have lower organ blood flow. The theoretical consequence of
this diminished flow may be a slower rate and probably lower extent of drug absorption
(Schwartz, 2003).
Alcohol absorption and bioavailability differs among women and men. Men will have
a lower alcohol level in blood than women after consumption of the same ethanol
concentration; this is because of increased GIT (gastrointestinal) enzyme (alcohol
dehydrogenase) activity, which results in faster degradation of ethanol in males (Baraona et
al., 2001).
2.4.9.4 Distribution:
Gender related differences in pharmacodynamic and pharmacokinetic result in
different responses to medications. More information is available on differences in
pharmacokinetic.
2.4.9.4.1 Factors influencing distribution:
It is well known that gender differences in the composition of body are present. Some
of these differences are due to difference in composition of body, fat% of body, BMI (body
mass index), volume of plasma, plasma protein-binding capacity and organ blood flow
(Beierle et al., 1999). All these stated factors affect the distribution of drug in the body
(Schwartz, 2004; Schwartz, 2007). It has been described that men have higher average body
weight, lower body fat%, larger average volume of plasma and higher average blood flow of
organs than women (Beierle et al., 1999; Pleym et al., 2003).
2.4.9.4.1.1 Body size and body fat:
150
There is smaller volumes of distribution and slower total clearance of many drugs in
women as compared to men due to differences in body sizes and on average females are
smaller than males. Lipophilic drugs may have higher volumes of distribution in females due
to higher fat% of body. This high body fat% persists until older ages (Schwartz, 2003). Males
are heavier with larger viscera (organs) and higher body mass index (BMI) than females
while doing calculation of bolus or loading dose, such differences must be considered
(Schwartz, 2004). To avoid unnecessary ADRs (adverse reactions), females should take
smaller doses (Schwartz, 2004; Schwartz, 2007).
2.4.9.4.1.2 Protein binding:
As a result of these disparities, important distribution differences between genders are
observed (Pleym et al., 2003). Other factor that may cause contribution to sex related
differences in drugs distribution is the protein binding, as sex hormones concentration affects
main groups of protein which are responsible for binding of the drugs. Therefore, changes in
distribution may occur between genders and during the menstrual cycle (Succari et al., 1990;
Walle et al., 1994).
2.4.9.4.1.3 Solubility:
2.4.9.4.1.3.1 Drugs; having water solubility:
As a general rule, water-soluble compounds are more widely distributed in men than
in women, since water content of men, normalized by the body weight, is about 15 to 20%
higher than women. Some examples of this situation are fluconazole (Carrasco and Francisco,
2011) and metronidazole (Carcas et al., 2001), in which distribution volume is bigger in
males as compared to females and such differences remain, although normalization by weight
is carried out (Carcas et al., 2001; Carrasco and Francisco, 2011).
Hydrophilic substances, such as alcohol (Schwartz., 2004) distribute into higher
volumes in men, causing lower initial concentrations in plasma and lower effects.
2.4.9.4.1.3.2 Drugs dissolved in lipids:
On the contrary, hydrophobic drugs are more widely distributed in women, due to
higher fat percentage. However, most of the times, changes in volume of distribution of the
drug are completely abolished when the parameter is normalized by the body weight. But the
main concern is that usually, dosage regimens employed for most of the currently used drugs
151
are not undergone normalization by individuals body weight, this situation may explain, at
least in part, the increased concentrations and therefore more frequency of side effects
observed in women.
Because the females have higher body stores of fat than males, which may results in
larger volume distribution of drug, which depends on hydrophobic and hydrophilic
characteristics of drugs. Because of having smaller volumes of fatty tissue in males than
females, lipophilic drugs such as benzodiazepines (diazepam) and neuromuscular blockers
(Xue et al., 1997) have shorter duration of action in males. As well as males are 30% less
sensitive to neuromuscular blocking agents (rocuronium) and need 22% larger doses than
females (Xue et al., 1997).
2.4.9.5 Metabolism:
2.4.9.5.1 Metabolic enzymes:
Drugs metabolism by liver occurs through Phase I, Phase II metabolism and by
combined conjugation and oxidative processes. Phase 1 includes reduction, hydrolysis and
oxidation through cytochrome P450's (2E1, 1A, 2D6,). Phase II includes conjugation,
glucuronidation, dehydrogenases, methyltransferases and glucuronyltransferases. These
processes are mostly cleared slower in females when compared to males (mg/kg basis). But
metabolism through N-acetyltransferase, CYP2C19, CYP2C9 and p-glycoprotein substrates
are more likely to be same in males and females. On the other hand, a number of CYP3A
substrates clearance seems to be a little bit slower (mg/kg) in men than in women (Schwartz,
2003). Some studies show that activity of CYP3A is higher in females compared to males
(Greenblatt and Lisa, 2008).
2.4.9.5.2 Phase-I reactions:
Many drugs are metabolized via phase-I reactions in liver and initial step (phase) of
metabolic process hydroxylates, reduces or oxidizes compounds via cyto-P450 (cytochrome)
system. Coumadin (warfarin) is amongst one of the drugs which shows different requirement
of dosage depending on gender. Sources show that females require between 2.5 mg and 4.5
mg (Whitley and Lindsey, 2009) less warfarin per week than men.
2.4.9.5.3 Phase-II reactions:
152
Polar conjugates of phase-I compounds (metabolites) or parent medications are
produced by phase-II metabolic processes for excretion through kidney. It occurs via
methylation, glucuronidation, acetylation or sulfation. These phase-II metabolic reactions are
usually faster in males, resulting some drugs to excrete faster; these drugs includes
caffeine (Schwartz, 2004), digoxin (Yukawa et al., 1997), fluorouracil (Schwartz,
2004), levodopa (Schwartz, 2004), mercaptopurine (Schwartz, 2004) and propranolol
(Inderal) [Walle et al., 1985; Schwartz, 2004].
2.4.9.6 Excretion:
Excretion of drugs can be carried out by several pathways; however, renal excretion is
one of the most important routes of drug excretion.
2.4.9.6.1 Filtration:
GFR (Glomerular filtration rate) is higher in males compared to females, moreover,
after normalizing GFR by the body size, a 10% difference remains (Gross et al., 1992) and
therefore, renal clearance may be diminished for a wide variety of drugs.
2.4.9.6.2 Re-absorption and secretion:
Concerning other mechanisms involved in the renal clearance, it has been reported
that sex-related differences in the tubular secretion and re-absorption present. It has been
established that clearance of taurocholate is increased in female rats when compared with
male rats, indicating an increased re-absorption process in females (Kato et al., 2002;
Schlattjan et al., 2005). Moreover organic anions excretion through urine in female rats is
increased in comparison with male rats (Kato et al., 2002, Kudo et al., 2002, Cerrutti et al.,
2002) indicating that renal clearance of organic anions may be increased in females.
2.4.9.6.3 Body weight:
As tubular re-absorption, tubular secretion and glomerular filtration are likely to be
slower in women than in men whether consideration done on basis of total body weight or on
mg/kg. So, in general renal clearance observed in women is lower than the values obtained in
men. Probably this may be due to the increased GFR observed in men that seems to have the
major role in the renal clearance of drugs. Sex and in some cases weight are incorporated as a
factor in algorithms using for estimation of GFR (Schwartz, 2003).
153
2.4.9.6.4 Physiological conditions:
There are several physiological conditions that are different between genders and that
are reflected in dissimilarities in the oral pharmacokinetics of drugs. Probably the two
parameters that are more affected by this situation are volume of distribution and systemic
clearance. Studies showed that main differences at molecular level in mammalian genders
exist which involved in renal function and metabolism of medications (Rinn et al., 2004).
2.4.9.6.5 Medicines:
Slow clearance of those drugs is seen in females which are eliminated unchanged
through urine (Schwartz, 2004) e-g, digoxin (Yukawa et al., 1997) and methotrexate
(Schwartz, 2004), both are excreted mostly through urine and having 13 and 17% faster
elimination in men, respectively. Many other drugs like cephalosporins (Schwartz, 2004),
aminoglycosides (Schwartz, 2004) and fluoroquinolones (Schwartz, 2004) have slower renal
elimination in females. So, these drugs should be received by females in lower doses.
2.4.9.7 Few examples about role of gender:
2.4.9.7.1 Pantoprazole, levofloxacin and losartan:
In order to contribute to the establishment of sex related differences in the PK
(pharmacokinetics), oral pharmacokinetics of three medications, pantoprazole, levofloxacin
and losartan were evaluated in women and men (Carrasco and Francisco, 2011).
2.4.9.7.1.1 Pantoprazole:
In the first study, oral pharmacokinetics of enteric coated formulation of pantoprazole
was evaluated in 52 healthy volunteers (26 females and 26 males). It was noted that high
levels in plasma were achieved in females, but after normalization of data by administered
dosage, these differences were disappeared; this was reflected in differences in several
pharmacokinetic parameters, Cmax, AUC and ClB. After normalization of values by the
individuals' body weight, it can be seen that volume of distribution is slightly lower in
women. These results seem to indicate that volume of distribution is reduced about 20% in
females as compared to males; this may be due to the body water differences between women
and men.
2.4.9.7.1.2 Levofloxacin:
154
In the second study, the oral pharmacokinetics of levofloxacin was evaluated in
female and male subjects. It was observed that achieved levels in plasma are about 20%
higher in women, but the difference completely disappeared when data were normalized by
the individual weight.
2.4.9.7.1.3 Losartan:
In the third study, oral pharmacokinetics of losartan was evaluated in 26 females and
26 males. It was observed that achieved levels in plasma are higher in females as compared to
males. After normalization of pharmacokinetic parameters by the body weight, an increased
clearance was observed in women.
2.4.9.7.2 Clindamycin:
Antimicrobial agent clindamycin is processed (metabolized) via CYP3A4. Drugs
pharmacokinetics processed via this pathway may be influenced by gender. But, there is lack
of information (data) about pharmacokinetic differences of clindamycin in males and
females. Gender difference in pharmacokinetics of clindamycin after oral administration was
evaluated. Oral dose of 600 mg clindamycin was taken under fasting conditions by 24
volunteers (11 males and 13 females) and at specific times in next twelve hours,
concentrations in plasma were noted. High levels in plasma were seen in females, however
after normalization of dosage by individuals' body weight, such differences were not seen,
which showed that there is no significant role of sex in the pharmacokinetics of clindamycin
(Carrasco et al., 2008).
2.4.9.7.3 Moxifloxacin:
Sex or age related pharmacokinetic differences are not exhibited by moxifloxacin. At
1st day after oral administration of 200-400 mg dose produces an effective antibiotic
concentrations (Sullivan et al., 2001).
2.4.9.7.4 Cefepime:
Cefepime belongs to broad-spectrum, fourth-generation cephalosporin. As
distribution volume and clearance of this drug shows no valuable differences among men and
women, so, for a given infection treatment, cefepime dosage should not be dependent on sex
(Barbhaiya et al., 1992).
155
As it can be seen, it is not possible to anticipate gender-related changes in drugs
pharmacokinetics after oral administration and therefore, case by case evaluation is important
in order to establish the adequate dosage regimen according to body weight and gender.
Although in most of the cases increased levels are seen in females as compared to males and
such difference is mainly due to the administration of higher normalized doses in women
(Carrasco and Francisco, 2011).
2.4.9.7.5 Cefuroxime:
In beagle dog, after intravenous (IV) infusion of 2 forms of this antibiotic i.e. cefuroxime
sodium and cefuroxime lysine showed insignificant difference (P > 0.05) in genders of dogs
and in the weight and age for different doses, this was studied in a population
pharmacokinetic and bioequivalence modeling. However cefuroxime lysine relative
bioavailability showed a significant difference (i.e. 𝑃 < 0.05) between men and women and it
was 1.05±0.18 (0.71-1.42). Therefore, in terms of extent and rate of absorption, both forms of
antibiotics (cefuroxime sodium and cefuroxime lysine) were bioequivalent. As well as among
these 2 antibiotics, there was found no sex related difference in the PK (pharmacokinetic)
data (Zhao et al., 2012).
2.5 Pharmacokinetic studies of cefixime:
Pharmacokinetic studies of cefixime are usually performed by microbiological assay
procedure and by HPLC. Both these methods are developed for the analysis or estimation of
concentration of cefixime in blood (plasma and/or serum), urine, bile and other biological
fluids (Falkowski et al., 1987; Neu, 1988).
2.5.1 Bioavailability of cefixime:
A number of pharmacokinetic studies of cefixime have been conducted in both
healthy and diseased children, adults and elders (Faulkner et al., l987b). The
pharmacokinetics of cefixime in healthy children following oral doses of l .5 or 3 mg/Kg of
the body weight was studied. They found the mean peak serum concentrations of cefixime to
be 0.64 and 1.l5 µg/ml after 4 hours of giving 1.5 and 3 mg/Kg, respectively (Motohiro et al.,
1986).
In another study, a single dose of oral cefixime of l .5 and 6 mg/Kg of body weight
was administered into healthy children. The mean peak concentrations of cefixime were l .34
156
and 2.5 µg/ml and the mean half-lives were 3.53 and 6.77 hours (for the dose of l .5 and 6
mg/Kg), respectively (Miyazaki et al., 1986).
Pharmacokinetics of cefixime in oral form was studied in healthy children in two
single doses of 3 and 6 mg/Kg. The mean peak concentrations of cefixime were l.7 and 2.72
µg/ml for these doses, respectively, attained at 4 hours after dosing. The elimination half-
lives were 3.09 and 3.11 hours for 3 and 6 mg/Kg, respectively (Iwai et al., 1986).
Another study was conducted in children with infection. Cefixime was administered
orally in single dose of 1.5 and 6 mg/Kg. The peak serum concentrations of cefixime were
0.65 µg/ml at 2-3 hours and 3.33 µg/ml at 4 hrs and the elimination half-lives were 2.4 and
2.5 hrs for the low and the high dose, respectively (Kurashige et al., l986).
Another study on cefixime pharmacokinetics was conducted in pediatric patients after
an oral dose of 1.5, 3 and 6 mg/Kg body weight (Fujii, 1986), the mean serum concentrations
at 12 hours were 0.2, 0.4 and 1.3 µg/ml, respectively; and the half-lives were ranging from
2.7 to 3.9 hours. Another study conducted in (US) pediatric patients using dose of 4, 6 and 8
mg per Kg body weight. The mean serum concentrations at 3.5 hour were 2.44, 4.07 and 3.91
µg/ml, respectively (Faulkner et al., l987b).
Cefixime was administered to healthy male adults (in a randomly ordered, double
blinded study with one week intervals between doses of 50 mg, 100 mg, 200 mg and 400
mg). Mean serum concentrations of cefixime were l.02 µg/ml, 1.46 µg/ml, 2.63 µg/ml and
3.85 µg/ml for doses of 50 mg, 100 mg, 200 mg and 400 mg, respectively; and times to
maximum peak were 2.7, 3.4, 3.9 and 4.3 hours for the respective doses. After 12 hours of the
drug administration, the mean concentrations of cefixime in serum were 0.33, 0.72 and l.13
µg/ml for doses of 100 mg, 200 mg and 400 mg per Kg body weight, respectively (Brittain et
al., 1985).
Faulkner et al. (l987b) studied the pharmacokinetics of cefixime after multiple oral
doses administered once or twice daily. Blood samples were collected on l, 8 and 15 days.
Mean peak concentrations were similar on all days with mean peak concentrations of l.64 to
l.8l µg/ml for the dose level of 200 mg twice daily and 2.64 to 2.96 µg/ml for the dose level
of 400 mg once a day. The bioavailability of cefixime was about 45% for a single oral dose
of both 200 and 400 mg. Extent of bioavailability was 26 µg/ml. hour for 200 mg oral
solution in healthy adults (Faulkner et al., l987a).
157
The serum t1/2 of cefixime in healthy subjects averages 3-4 hours but in some normal
volunteers it may range up to 9 hours and this plasma half life is independent of drug dosage
form. In elderly patients, at steady state, average AUCs are about 40% more than the average
AUCs at steady state, in other human healthy adults (Baltimore, 2005).
2.5.2 Distribution of cefixime:
Protein binding of cefixime is about 70% (Bialer et al., 1986). Volume of distribution
of cefixime is not concentration dependent and was ranged from 0.5 to 26 mg/L. The free
fraction of cefixime in plasma tended to increase with decreasing renal function but this rise
did not reach statistical significance (Faulkner et al., l987b). After absorption of cefixime, it
is distributed into all tissues including the respiratory tract and inflammatory exudates
(Grellet et al., 1989) whereas it penetrates to a lesser extent into aqueous humor and tonsils of
the children (Begue et al., 1989). Cefixime readily penetrates into cerebrospinal fluid (CSF)
of children with meningitis whereas penetration into CSF of healthy children is poor (Nahata
et al., 1993). Following 100 mg administration of oral cefixime to the pregnant women,
plasma concentrations were in between 0.18 and 0.8 mg/L at 0.5 to 5 hours after ingestion.
Through-out this period, the concentration in serum of umbilical cord was about 15% to 30%
of that in the maternal plasma (Takase et al., 1985). Serum or plasma protein binding is not
dependent of the concentration and the bound fraction of drug is about 65%. In a multiple
dose study of a research formulation that was less bioavailable than suspension or Tablet, a
little accumulation of drug was found in serum or urine after 14 days dosing (Baltimore,
2005).
2.5.3 Elimination of cefixime:
Cefixime has affinity to reach in renal parenchyma. Penetration of cefixime in renal
parenchyma does not much vary as compare to cortex and medulla. The result showed that
cefixime concentration has rapidly decreased in serum as compare to tissue concentration of
cefixime (Leroy et al., 1995). Decreased creatinine clearance caused an increase in
elimination half-life and decrease in apparent total body clearance (renal and non-renal) and
protein binding.
Cefixime is excreted mainly in the bile (60%) as unchanged form and also by the
kidney (40%) partly (Barre, 1989). Low urinary recovery rate and the high cefixime
concentration in the bile and in gallbladder tissues indicate extensive elimination of this drug
158
by liver (Tanimura et al., 1985). The elimination half life varies between 3 to 4 hrs (Brittain
et al., 1985; Saito, 1985; Faulkner et al., l987b). Total systemic clearance of the drug was
about 4.41 ml/min, following single dose of 200 mg intravenous cefixime in healthy human
subjects with renal clearance of about 40% (Faulkner et al., 1988). About 50% of the
excretion of absorbed dose occurs in the urine in unchanged form in 24 hours. It was found in
animal studies that cefixime is also excreted in bile in excess of the 10% of the dose
administered (Baltimore, 2005).
2.5.4 Biliary excretion of cefixime:
The main pharmacokinetic characteristics of cefixime in healthy subjects are
prolonged elimination t1/2 and extra-renal processes for drug clearance, as clearance by renal
pathway is about only 40% of the total systemic clearance (Faulkner et al., 1988).
For this cephalosporin, no drug metabolite which is biologically active has been found
in serum/plasma, biliary or urinary excretion. Biliary excretion of cefixime was analysed in
10 patients with T-tube drainage of common bile duct after cholecystectomy. Cefixime's
maximum concentration reached in the bile was 56.9±70 mg/liter following a single oral dose
of 200 mg, which was about 20 times greater than the peak serum concentration, i.e. 2.3±0.85
mg/liter. Results showed that an oral dose of 200 mg of cefixime provided the consistently
higher drug levels in the bile than MICs for the most frequently recovered members of the
family Enterobacteriaceae in biliary tract infections and these drug levels were maintained for
over 20 hrs after dosing. Clinical trials are required to find out usefulness of this
cephalosporin in both the prophylaxis and treatment of infections of the biliary tract
(Westphal et al., 1993).
2.5.5 Penetration and bactericidal action of cefixime in the synovial fluid:
Cefixime is indicated to treat otitis media, upper and lower RTIs and infections of the
urinary tract when these infections are caused by susceptible organisms (Goto et al., 1985).
The role of cefixime in prophylaxis and treatment of joint infections was not studied till 1996.
A study was conducted to verify the concentration of cefixime in the joint fluid following
oral administration of the agent. The penetration of oral cefixime was examined into the
synovial fluids of 16 patients (mean age, 50.6 years) who underwent joint taps for rheumatic
noninfectious disorders. The patients were administered a single 400 mg dose. Cefixime level
in serum and in joint fluid samples were measured by HPLC and the bactericidal activities of
159
these fluids against three isolates each of Haemophilus influenza and Escherichia coli were
examined. The highest concentrations in serum and synovial fluid were achieved 4 hr
following drug intake, the mean values being 2.8 and 2.03 mg/ml, respectively. Effective
bactericidal activities (bactericidal titer>1:2) against E. Coli and H. Influenza were
demonstrated in serum and joint fluid up to 10 hr following oral intake of cefixime. These
results suggest that cefixime penetrates well into joint fluid, achieving levels above the MIC
for E. coli lasting as long as 10 hr and levels above the MIC for H. influenza lasting up to 24
hr after administration. Good bactericidal activity against susceptible bacterial isolates was
observed for at least 10 hr after dosing. So, in this study conducted to check the cefixime
ability to reach synovial fluid, the conclusion was that cefixime can penetrate well in synovial
fluid and after 10 hours administration of cefixime it has good bactericidal activity (Somekh
et al., 1996).
2.5.6 Influence of disease state on cefixime pharmacokinetics:
2.5.6.1 Hepatic dysfunction:
The pharmacokinetic studies of cefixime were conducted in hepatic patients with
varying degrees of disease. The pharmacokinetics of cefixime was studied in-patient with
severe impairment of liver function. They reported that the Cmax and AUC were did not differ
by degree of impairment. The time for maximum concentration was prolonged. The volume
of distribution was increased possibly due to ascites and hypoalbuminemia (Singlas et al.,
1989).
2.5.6.2 Renal dysfunction:
Cefixime may be given in state of renal impairment. In patients having 60ml/min or
more creatinine clearance, normal dose and schedule may be employed. Total 75% of the
standard dosage may be administered at the standard dosing interval to the patients having
creatinine clearance 21 to 60 ml/min or to the patients who are on hemodialysis (i.e. 300 mg
daily). For the patients with clearance < 20 ml/min or for patients who are on ambulatory
peritoneal dialysis continuously, half (50%) of the standard dosage is recommended at
standard interval of dosing (i.e. 200 mg a day). Both peritoneal dialysis and hemodialysis do
not remove the significant amount of drug from body (Baltimore, 2005).
Cefixime pharmacokinetic studies have been conducted in renal patients with varying
degrees of dysfunction or impairment and in subjects undergoing peritoneal or hemodialysis
160
(Guay et al., 1986). Single dose of 400 mg were administered to these patients. The
absorption was delayed to 4 hours. Peak serum drug concentration in patients having
creatinine clearance of 41-60 ml/min averaged 7.48 µg/ml and it was 9.5 µg/ml in patients
having creatinine clearance in range of 5-20 ml/min. The t1/2 increased from 3 hours in
normal subjects up to 6 hours in patients with clearance of creatinine ranging 41 to 60 ml/min
and to 11.5 hours in individuals with clearances of 5 to 20 ml/min.
Pharmacokinetic studies of oral cefixime were studied in children having urinary tract
infection after single dose of 8 mg/Kg of the body weight. The mean peak drug concentration
in plasma was 4.04 µg/ml achieved at 3.2 hours after dosing. The mean area under time
versus drug concentration curve was 33.07 µg.hr/ml and the mean elimination t1/2 was 3.91
hours. The mean total apparent clearance was 4.74 ml/min/kg (Mamzoridi et al., 1996). In
addition, the effect of renal dysfunction on cefixime disposition after single oral dose of 200
mg was also studied. In ureaemic patients, maximum concentration and time for maximum
concentration were slightly increased than control and the half-life was also increased up to
12-14 hours; the apparent volume of distribution was decreased (Dhib et al., 1991).
2.5.7 Bioequivalence and pharmacokinetic parameters of cefixime:
Various bioequivalence studies of cefixime have been reported in literatures which
show the existence of bioequivalence in cefixime products of different manufacturers and
different dosage forms.
2.5.7.1 Bioavailability study of cefixime:
As oral cephalosporins are inactivated by gastric acid and due to their hydrophilicity
they are unable to traverse the mucosal barrier of small intestine, so, these are the reasons due
to which cephalosporins have poor absorption generally. However newer oral cephalosporins
have quite varied oral absorption. Although 400 mg capsule cefixime has lower urinary
excretion, the absolute bioavailability is higher, 40% to 52% (Brogden and Campoli-
Richards, 1989).
After a 400 mg dose, maximum plasma concentration of cefixime in adults generally
ranges from 3 to 5 mg/L (Brogden and Campoli-Richards, 1989). Cefixime is slowly
absorbed amongst the newer oral cephalosporins; with peak absorption after two hours.
Penetration into the tissue fluids exceeds 130%. The elimination t1/2 is generally about 3
hours and it is prolonged in the patients having impaired kidney function e.g. in patients who
161
have creatinine clearance less than 20 ml/min (Low, 1995). Protein binding capacity for
cefixime is about 65% (which is concentration independent). Biotransformation or hepatic
biotransformation studies show that urinary excretion (unchanged) in 24 hr is approximately
50%.
These findings support the usage of this 3rd generation agent once a day or twice daily
for lower respiratory tract and other infections (Low, 1995).
Pharmacokinetic of a broad-spectrum cephalosporin, oral cefixime was assessed in 12
healthy subjects after 50, 100, 200 and 400 mg in single doses. The values of Cmax were 1.02,
1.46, 2.63 and 3.85 µg/ml after the four respective doses. At 12 hours, respective mean serum
levels were 0.16, 0.33, 0.72 and 1.13 µg/ml. The value of Vd averaged 0.1 L/kg body weight
and the t1/2-β was 3 hours for all the doses. The AUCs were 7.01, 11.4, 22.5 and 36.4
µg.hr/ml, respectively, for the four doses. Serum ClB averaged 0.4 mg/min/kg and mean
urinary recovery for the four respective doses was 21%, 19%, 20% and 16% in 24 hour
(Brittain et al., 1985).
2.5.7.2 Different brands of cefixime:
Comparative bioavailability of two cefixime oral formulations was evaluated in total
24 healthy males. The trial was planned as a randomized, open, two-sequence, single-blind
and two-period crossover study. In fasting condition, each subject received 400 mg cefixime
(reference and test formulation) Tablet as single oral dose, on two treatment days. Wash out
duration was of one-week. A sensitive and rapid HPLC technique with UV detector was used
to analyse plasma concentration of cefixime. Pharmacokinetic parameters used were AUC(0-
infinity), AUC(0-24), t1/2, Cmax and Ke. Mean AUC(0-infinity) was 45008.7±10989.9 and
45221.3±2155.7 ng.hr/ml and Cmax was on average 4746.9±1284 ng/ml and 4726.3±1206.9
ng/ml for test and the reference products, respectively. Statistical difference was not seen for
area under time-plasma drug concentration curve and for Cmax of both the reference and test
formulations. The 90% calculated confidence intervals, by ANOVA, for the mean
test/reference ratios of AUC(0-24), AUC(0-infinity) and Cmax of cefixime were in their
bioequivalence range (94%-112%). So, both formulations were bioequivalent to each other
(Zakeri et al., 2008).
A study was conducted on Comparative bioavailability of cefixime (Winex vs
Suprax) suspension (100 mg/5ml) in male healthy volunteers. Suprax was used as reference
162
product. Twenty four healthy male volunteers received single dose of 200 mg of both brands
orally, on two treatment days with an overnight fasting of ten hours and washout period was
of one week. A Balanced and randomized two-way crossover design was employed. Blood
samples were withdrawn for 16 hours at different time intervals. A sensitive HPLC assay was
applied to analyze cefixime concentration in serum/plasma.Pharmacokinetic parameters were
calculated by non-compartmental standard method. The determined parameters were T max,
AUC(0-infinity), AUC(0-t), Kel, Cmax, t1/2 and Cmax/AUC(0-infinity). The 90% confidence intervals of
mean values of pharmacokinetic parameters such as, AUC(0-t), AUC(0-infinity), Cmax and
Cmax/AUC(0-infinity) were within 80 to 125% which was an acceptable range of bioequivalence
(using log-transformed data). The 90% confidence intervals calculated by ANOVA for the
mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were 88.93-
107.10%, 89.09-107.11%, 89.63-108.58% and 96.85-105.29%, respectively. Both the test
formulation (winrex) and reference formulation (suprax) were bioequivalent (Asiri et al.,
2005).
Bioequivalence of two cefixime capsule 100 mg brands (Alpha-cefixime and Suprax)
has been investigated in 24 healthy volunteers in Korea, divided into 2 groups. A randomized
cross-over study was employed. Between the doses, the washout period was one week.
Cefixime concentrations in plasma, collected at predetermined intervals of time, were
analyzed by HPLC using UV detector. Bioequivalence parameters calculated were AUC (t),
Tmax and Tmax and for statistical analysis of these parameters ANOVA method was employed.
According to the results the differences in AUC(0-t), Cmax and Tmax of these two products were
-3.91%, -2.23% and -3.18%, respectively, when they were calculated against reference drug.
All the parameters fulfilled the KFDA criteria for bioequivalence, which indicated that
Alpha-cefixime capsule (Alpha Pharmaceutical Co.) and Suprax capsule (Dong A.
Pharmaceutical Co.) were bioequivalent (Choi and Jin, 2007).
In study of Bioequivalence of cefixime, two brands of cefixime capsule 200 mg were
given as single administration as test and reference to 20 healthy males in randomized
crossover design. Cefixime serum concentration was determined by high performance liquid
chromatography and bioassay. Program 3P97 was used for analysis of data and calculation of
data was done on the basis of one-compartment model. Pharmacokinetic parameters which
were determined after HPLC analysis for both reference and test capsules were as follows:
Cmax (2.317±0.536 and 2.287±0.492 mg.L-1); Tmax (4.1±0.7 and 4.3±0.7 hr); AUC(0-16)
(17.251±5.087 and 16.954±4.536 hr.mg.L-1); AUC(0-∞) (l8.386±4.559 and 18.138±3.931
163
hr.mg.L-1). The pharmacokinetics parameters calculated after bioassay for test and reference
products were as follows: Cmax (2.437±0.495 and 2.361±0.435 mg.L-1); Tmax (4.13±0.65 and
3.90±0.45 hr); AUC(0-16) (18.741±3.931 and 18.064±3.350 hr.mg.L-1); AUC(o-∞)
(20.109±4.497 and 19.403±3.693 hr.mg.L-1); respectively. No significant difference was
found there. Relative bioavailability of group determined by HPLC and bioassay was
101.53±18.21% and 103.30±15.78%. All the results showed that both preparations were
bioequivalent. HPLC and bioassay methods both were interrelated (Ying et al., 2003).
2.5.7.3 Different dosage forms of cefixime:
Study on bioavailability and bioequivalence of cefixime in healthy volunteers was
conducted. Cefixime 200 mg Tablet and capsule (cefspan) was given as single oral dose to 20
healthy volunteers in randomized crossover study. Concentration of cefixime in plasma was
determined by HPLC. Computer program 3p97 was used for calculation of pharmacokinetics
parameters and bioavailability. The linear range of cefixime was 0.1-5.0 µg/ml (r=0.9993).
The values of t1/2ke were (4.98±0.58) hr and (5.28±0.77) hr; of Tmax were (4.7±0.6) hr and
(4.6±0.9) hr andof Cmax were (3.38±0.9) μg/ml and (3.29±0.87) μg/ml for cefixime Tablets
and cefixime capsules, respectively. The relative bioavailability of cefixime Tablets to
cefixime capsules was 102.8±19.7%. These results indicated that two preparations were
bioequivalent (Lan-Ying et al., 2004).
In a bioequivalence study of Tablet and sachet of oral cefixime 200 mg as single
doses in 18 healthy human volunteers (males), obtained data demonstrated that two
formulations were bioequivalent. Reference formulation (Tablet Oroken 200 mg) and test
formulation (novel Orokensachet 200 mg), were tested in crossover study. Statistical
differences were neither observed for Cmax nor for AUC at confidence interval of 90% in-
between mean Cmaxand mean AUC of the sachet and Tablet. So, both preparations were
within bioequivalence interval (0.8-1.25). No evidence was found for difference in-between
t1/2 (serum half-life) and Tmax (time to reach Cmax) of two formulations. Moreover, for both
formulations, unchanged cefixime in comparable amounts were eliminated by urine, over
same time frames. Biological and clinical tolerability for these both formulations were also
excellent. Result in this study shows bioequivalence for Tablet and sachet forms of cefixime
in terms of rate and extent of absorption (bioavailability). If patient is unwilling or unable to
take cefixime Tablet, the formulation of cefixime sachet may be of considerable value for
him (Evene et al., 2001).
164
A comparative pharmacokinetics study of domestic and imported cefixime in
volunteers in 3 dosage forms (fine granules, capsule and Tablet) were performed in 30
volunteers. There was no statistical difference in the results of domestic and imported
cefixime in different dosage forms for following listed mean parameters: Cmax 2.17-2.62
μg/ml, Tmax 3.4-4.6hr, AUC 25.8-29.5μg.hr/m1, t1/2ke 3.50-4.43hr, MRT 7.47-8.15hr.
Bioassay technique was used for determination of plasma level of drug. From the results it
was concluded that there was no significant difference between domestic and imported
cefixime dosage forms (Jieying et al., 1996).
2.5.7.4 Role of diet (fasting and non-fasting conditions):
Food has been shown to have a minimal effect upon peak serum level with 4.22 µg/ml
achieved after ingestion of 400 mg with food and 4.24 µg/ml when 400 mg was ingested
while fasting. There was prolongation in the time to achieve maximum absorption from 3.78
hours to 4.8 hours with food. However, AUC were statistically not different, 32 and 30.8
µg.hr/ml, respectively (Faulkner et al., l987a).
Pharmacokinetic profile of cefixime was studied in healthy volunteers in fasting and
non fasting state along with detection of cefixime in serum by HPLC method. Cefixime200
mg was given to eight healthy volunteers as single oral dose, in fasting and non-fasting (after
meal) state, the mean maximum concentration in plasma were 2.7±0.9 and 1.7±0.4 mg/L, the
mean t1/2ke were 3.7±0.4 and 3.3±0.7 hours. The mean AUC were 25.4±8.5 and 13.9±4.0
hr.mg/L while 23.7±7.5% and 13.6±4.5% of the drug were excreted via urine within 24hr.
The mean serum concentrations at 12 hr were 0.83±0.26 and 0.45±0.18 mg/L respectively.
The pharmacokinetic parameters of cefixime among volunteers were significantly different
such as of Cmax, AUC and urinary excretion rates in fasting and after meal state. HPLC
method employed for cefixime detection was accurate and reproducible. The serum drug
concentrations analyzed by HPLC were highly correspondent with that of obtained by
bioassay (Yaoguo et al., 1994).
2.5.7.5 Comparative pharmacokinetic:
In a comparative pharmacokinetic study of orally administered ceftibuten, cefixime,
cefuroxime axetil and cefaclor; Tmax and t1/2 were relatively higher for ceftibuten, resulting in
a 3.5 times higher AUC than cefixime, cefuroxime axetil and cefaclor. Four oral
cephalosporins can be compared on basis of these pharmacokinetic data; however,
165
comparative susceptibility data must also be under consideration. The mean clearances were
similar for the cefixime, cefuroxime axetil and cefaclor in the range of 20.4–27.0 L/hour;
ceftibuten had approximately 4-fold less clearance, 5.45 L/hour. The serum half-lives were
prolonged for ceftibuten (2.35 hr) and cefixime (2.38 hr) in comparison with cefuroxime
axetil (1.30 hr) and cefaclor (0.693 hr). So,these drugs differed in maximum concentration,
time to peak serum drug level, area under the time versus concentration curve and apparent
volume of distribution.
2.6 Cefixime and other drugs:
Drug–drug interactions are important issue today in health care. It is realized now that
alteration in the metabolic enzymes, present in liver and other extra-hepatic tissues can
explain many of these drug–drug interactions and most of hepatic cytochrome P450 (P450 or
CYP) enzymes are affected by previous administration of other drugs resulting in the major
pharmacokinetic interactions between drugs. In co-administration of drugs, some can act as
potent enzyme inhibitors whereas other drugs are enzyme inducers. But reports of enzyme
inhibition are much more common. For giving multiple-drug therapies appropriately it is very
important to understand the mechanisms of this enzyme inhibition or enzyme induction. In
future, it may help physicians for identification of the individuals who are at greatest risk for
drug interactions and adverse events (Tanaka, 2002).
2.6.1 Treatment of uncomplicated UTIs in women:
Cefixime and Ofloxacin:
Cefixime, a broad spectrum antibacterial agent, is effective against certain
uropathogens. Maximum concentrations of 3 to 4 µg/ml are achieved in serum after 3-4 hr of
a cefixime Tablet of 400 mg. Serum half-life (3-4 hr) is longer than other oral β-lactam
antibiotics. Additionally, after single dose of 400 mg orally, a concentration of cefixime in
urine for 90% of the most common urinary pathogens is above the MICs (Faulkner et al.,
1987b).
In woman uncomplicated cystitis is apparently treated by approximately three day
regimen of antibiotics. Cure rates of this regimen can be compared with that of the longer
therapy course, along with incidence of low adverse effects observed with the single dose of
therapy (Johnson and Stamm, 1989).
166
Single-dose or short-course or 3-day regimen of quinolones and cotrimoxazole are as
efficacious as the other longer therapy courses (Hooton et al., 1991); however, comparable to
course of 3-day or single-dose, β-lactams were found more effective when administered for
five or more days (Norrby, 1990).
3-day regimen of ofloxacin (200 mg two times a day) and cefixime (400 mg once a
day) to treat UTIs in women (uncomplicated cystitis) were compared in a randomized double
blind study. Clinically cure rates for two groups of women were 81% and 84% after 4 weeks
and 89% and 92% after 7 days whereas microbiologically cure rates (free of bacteriuria) for
these two groups of women were 77% and 80% after 28 days and 83% and 86% after 7 days.
The three days ofloxacin regimen appeared to be as effective as the three day regimen of
cefixime for treatment of uncomplicated cystitis in women (Raz et al., 1994).
2.6.2 Treatment of uncomplicated gonorrhea in men:
Cefixime versus amoxicillin plus probenecid:
In a randomized study, a 3 g amoxicillin plus 1 g probenecid cured 44 of 46 men in
comparison with 96 cures of 97 in whom receiving a single 800 mg-cefixime for treatment of
uncomplicated gonococcal urethritis. Both of these regimens were not effective against
infection coexisting with Ureaplasma urealyticum and Chlamydia trachomatis. Cefixime was
tolerated well with mild and self limited adverse effects (David et al., 1990). Neisseria
gonorrhoeae has high susceptibility to cefixime In-vitro (Bowie et al., 1987). Cefixime had
interaction with probencid; therefore, its concomitant use with probencid should be avoided
(Jayatilaka and Kinghorn, 2006).
2.6.3 Effect of an (aluminum and magnesium containing) antacid on pharmacokinetics
of cefixime:
Aluminum and magnesium containing non systemic antacids are widely used for
treatment of disorders of gastrointestinal tract. When co-administered, antacids interfere with
absorption of many drugs, including cefuroxime axetil, fluoroquinolone and tetra-cycline
antibiotics (Sommers et al., 1984; Lode, 1988).
In an interaction study in dogs, antacids decreased significantly the bioavailability of
oral cefixime, however, no significant reduction in oral bioavailability of cefixime was noted
with co-administration of an aluminum-magnesium antacid (Healy et al., 1989).
167
2.6.4 Enhancement in bioavailability of cefixime by nifedipine in human:
Absorption rate of cefixime was increased significantly by nifedipine. Cefixime has
absolute bioavailability of 31±6% when given alone while 53%±1% when present with
nifedipine. It is concluded that apparently an active process plays an important role in
absorption of cefixime in humans which may be modified by a CCB (calcium channel
blocker) i.e. nifedipine (Duverne et al., 1992). In rats, as similar to the amoxicillin,
absorption of cefixime from intestine occurs with help of an active transport mechanism
which involves a pH-dependent dipeptide transporter (Tsuji et al., 1987a,b).
2.6.5 Interaction between beta-blocker antihypertensive and β-lactam antibiotic:
Bioavailability of beta lactam antibiotic can be increased by using ca+2 channel
blocker. The study was conducted in human being. The result indicated that by using ca -
channel blocker there was an increase in intestinal epithelial cell uptake of cefixime (Wenzel
et al., 2002).
2.6.6 Carbamazepine:
Carbamazepine levels are elevated after concomitantly administration of cefixime.
Drug monitoring may help to detect the alteration in carbamazepine plasma-concentrations
(Baltimore, 2005).
2.6.7 Warfarin and anticoagulants:
The influence of cefixime was reported on liverenzymes (cytochrome P450).
Cefixime could interact with warfarin and increases its anticoagulant response (Lakshmi et
al., 2012). When cefixime is concomitantly administered, prothrombin time increases without
or with any clinical bleeding (Baltimore, 2005).
2.6.8 Cefixime bests ceftriaxone:
Both oral cefixime and intramuscular ceftriaxone do the trick against uncomplicated
Neisseria gonorrhoeae cervicitis in adolescents. But cefixime, which is the only one of the
single-dose antibiotics recommended for patients younger than 17, has several other
advantages as well: Although more expensive than ceftriaxone, cefixime is painless, simpler
to administer and minus the risk of needle stick (Lippincort and Wilkins, 1996).
168
The treatment of quinolone unresponsive or resistant infection due to S. typhi is not
clear. A 3rd-generation parenteral cephalosporin, such as ceftriaxone, is a convenient choice.
An oral third generation cephalosporins, as cefixime, may be a reasonable option for less
seriously ill patients (Girgis et al., 1995a,b).
2.6.9 Drug / laboratory-test interactions:
In tests using nitroprusside, a false +ve reaction may result for the ketones in urine but
it was not with those using nitroferricyanide (Baltimore, 2005).
False +ve reaction may occur for glucose in the urine using Fehling's solution or
Benedict's solution, when cefixime is administered. Glucose tests which are based on the
enzymatic glucose oxidase reactions are recommended to be used (Baltimore, 2005).
During treatment with other cephalosporin antibiotics, a false +ve direct Coombs test
has been reported; so, a positive Coombs test may be due to the drug (Baltimore, 2005).
2.6.10 Food interactions:
Food affect the bioavailability of certain first, second and third generation
cephalosporin antibiotics such as cefaclor, ceftibuten etc. But the bioavailability of first
generation cephadroxil and cephalexin, cefprozil of second generation cephalosporins and
cefixime that belongs to third generation cephalosporin was not affected by the food (Levison
and Levison, 2009). A decrease in rate of absorption is observed when stomach is empty but
extent of absorption does not alter.
2.7 Determination of cefixime:
2.7.1 Estimation of cefixime in body fluids:
Many different assay procedures are reported in literature to estimate cefixime in
formulation, blood and urine etc. These include many different methods but the most
common used methods are:
Bioassay or Microbiological method or also called the disc diffusion method (Brittain,
1985; Nies, 1989; Eldalo et al., 2004).
Recently high-pressure liquid choromatography (HPLC) has found application in
determination of drugs in biological fluids or body fluids and several methods for analysis of
169
antibiotics have been reported. Different HPLC procedures for quantification of cefixime in
serum and urine were developed (Guay et al., 1986; Westphal et al., 1993; Leroy et al., 1995;
Zendelovska et al., 2003; Asiri et al., 2005; Adam et al., 2012).
2.7.2 Different methods of analysis of cefixime:
Reviewing the literature revealed that several methods are developed to quantify the
cefixime in pure form, in pharmaceutical formulations / preparations or in biological samples,
whether as single active ingredient or in combination with any other drugs. These methods
include HPLC, high performance thin layer chromatography (HPTLC), spectrophotometric,
spectrofluorimetric, electrophoretic and voltammetric methods.
2.7.2.1 HPLC procedures for determination of the cefixime formulations:
British Pharmacopoeia (2011) stated HPLC methods for analysis of cefixime and
related substances on column C-18 (12.5 cm x 4 mm) at 40 °C temperature with
tetrabutylammonium hydroxide (pH adjustment to 6.5 with dilute phosphoric acid) and
acetonitrile (3:1) as a mobile phase with 1 ml/min of flow rate and UV detection at 254 nm.
United States pharmacopoeia (USP, 2007) recommended a similar HPLC method but
the reference standard and the sample were dissolved in pH 7 phosphate buffer.
Several methods of HPLC have been developed to determine cefixime in bulk and in
pharmaceutical dosage forms. All of these methods have used reversed phase C-18 columns
but with different dimensions (4 and 4.6 mm internal diameter, 10, 15 and 25 cm length).
Different mobile phases have been used (phosphate buffer with acetonitrile, phosphate buffer
with methanol, tetrabutylammonium hydroxide with acetonitrile, methanol with water and
acetonitrile with methanol with ammonium acetate). In these methods flow rates of 0.8, 1and
2 ml/min were used and detection was done by UV absorption at different wavelengths (254
nm, 285-287 nm and 295 nm) [Gonzalez-Hernandez et al., 2001; Shah and Pundarikakshudu,
2006; Arshad et al., 2009; Saikrishna et al., 2010; Raj et al., 2010; Pasha et al., 2010].
Several Reverse Phase HPLC methods were validated and developed with UV
detectors for simultaneous analysis of cefixime with other drugs in the same dosage form. For
example, a RP-HPLC procedure, using C-18 column, has been validated to simultaneously
determine cefixime and cloxacillin in Tablets. Mobile phase was prepared by mixing
phosphate buffer (of pH 5), acetonitrile and methanol and 2ml/min was the flow rate for
170
mobile phase with U.V. detection at 225-nm. Method was observed linear in range of 160-
240 µg ml-1 and 400-600 µg ml-1 with retention times 5.6 and 6.2 min for cefixime and
cloxacillin, respectively. It was concluded that the method was rapid and sensitive
(Rathinavel et al., 2008).
Developmentand validation of a similar RPHPLC procedure for simultaneous
detection of cloxacillin and cefixime in Tablets was performed by using C-8 column, mobile
phase of acetonitrile and tetrabutylammonium hydroxide, flow rate with 1 ml/min alongwith
Ultra-Voilet detection at 225 nm. This method was found linear in range of 10-50 µg ml-1 and
25-125 µg ml-1 and retention time 5.75 and 11.9 min for cefixime and cloxacillin,
respectively (Wankhede et al., 2010).
For determination of combination of dicloxacillin and cefixime in Tablets, a RP-
HPLC method was developed and validated. C-18 column was used and mixture of
acetonitrile and potassium hydroxide buffer as mobile phase with ultraviolet detection at 220
nm and flow rate of 1 ml/min. Linearity obtained in the range of 60-140 µg.ml-1 (Kathiresan
et al., 2009).
In an RP-HPLC method to detect cefixime and ornidazole combination in the Tablet
dosage form, C-18 column was used and acetonitrile with 40 mM KH2PO4 as a mobile phase
and its flow rate was 1 ml/min at 310nm UV detection. Retention time of cefixime and
ornidazole were 2.75 min and 6.67 min, respectively (Sudhakar et al., 2010).
In another method of HPLC analysis of cefixime and ambroxol simultaneously by
using C-18 column and actonitrile with methanol was used as mobile phase. Ultravoilet
detector was used at 254 nm with 1.68 and 3.7 min retention time and linearity ranges from
4-18 and 4-28 µg/ml, respectively, for cefixime and ambroxol (Deshpande et al., 2010).
In development of a HPLC estimation of cefixime and cefuroxime axetil in bulk and
in dosage form by using column of C-18 with U.V. detection at 254 nm, a mixture of
methanol and water was used as mobile phase (Raj et al., 2010).
In description of a RP-HPLC method to determine cefixime and erdosteine
simultaneously in dosage forms, C-8 column was as stationary phase while mobile phase was
a combination of tetrabutyl ammonium hydroxide (having pH adjustment to 6.5) with
acetonitrile in a ratio of 2:1. Detection was done by UV at 254 nm, linearity obtained in the
171
range of 2-22 µg ml-1 for cefixime and 3-33 µg ml-1 for erdosteine, with retention time 10
min for cefixime and 5.4 min for erdosteine (Dhoka et al., 2010).
A RPHPLC method was used for the quantification of cefixime and potassium
clavulanate simultaneously in Tablet dosage forms. C-18 column was used as stationary
phase and mobile phase was composed of methanol and phosphate buffer and detection was
at 220nm. Result values were found in linear range of 20-100 µg ml-1 and 12.5-62.5 µg ml-1
and retention time 7.3 and 2.4 min for cefixime and potassium clavulanate, respectively
(Kumudhavalli et al., 2010).
Another RPHPLC method was described to simultaneously measure the cefixime and
potassium clavunate in Tablet forms, using a mixture of methanol and tetra butyl ammonium
hydroxide solution as mobile phase with 1 ml/min flow rate at 40ºC. The detection of
compound was done at 230 nm and 4.63 min and 11.89 min was the retention time for
potassium clavulanate and cefixime, respectively, and linearity was 10-180 µg ml-1 for
clavulanic acid and 10-360 µg ml-1 for cefixime (Basu et al., 2011).
According to a published RPHPLC procedure for the simultaneous estimation of
cefixime and ofloxacin in Tablets, C-8 neosphere was the column used and methanol with
potassium dihydrogen phosphate buffer was the mobile phase used. Detection was done at
290nm. Linearity was found in range of 1-10 µg ml-1 for both of these drugs (Khandagle et
al., 2011).
A similar method for separation and detection of cefixime and ofloxacin in Tablets
was developed with some differences in column and mobile phase used. The column used
was C-18 and mobile phase used was methanol and 25Mm phosphate-buffer (40:60 v/v) and
UV detection at 290 nm. Respective retention times for cefixime and ofloxacin were 2.5 and
7.8 min. The method was linear in range of 5-25 µg ml-1 for both drugs (Natesan et al., 2011).
Moreover, several RPHPLC methods were developed to estimate cefixime in the
biological fluids:
In a published RPHPLC method for determination of cefixime in serum of human, the
method was linear from 0.1 – 30 µg ml-1 for serum assay and from 5 – 100 µg ml-1 for the
urine assay (Falkowski et al., 1987).
172
In another developed RPHPLC method for analysis of five oral cephalosporins in
human serums, mobile phase was prepared by mixing methanol: monobasic phosphate buffer
(20:80), flow-rate 2 ml/min in C-8 column and ultraviolet detection was at 240 nm. The
authors concluded that this method has advantages over previous methods in that the same
conditions are used for five drugs and at clinically significant concentrations (McAteer et al.,
1987).
A published RP-High Pressure Liquid Chromatography method for analysis of
cefixime and cefotaxime simultaneously in the plasma, utilized a column of C-8 and mobile
phase of methanol and KH2PO4 (pH 2.2) (25:75, v/v). pH of buffer was adjusted to 2.2 (by
additionof small quantity of concentrated ortho-phosphoric acid). Detection was carried out
by UV and the method was found to be linear over the concentration range 0.2-12 µg ml-1 for
cefixime and 0.2-50 µg ml-1 for cefotaxime in samples of plasma (Zendelovska et al., 2003).
An HPLC analysis was developed to analyze cefixime in blood / plasma to compare
two pharmaceutical preparations (Pisarev et al., 2009).
A fast HPLC method was published for analysis of third generation three
cephalosporins including cefixime in human plasma. The method was performed by use of C-
18 column along with methanol and phosphate buffer as mobile phase having 1 ml/min flow
rate and UV detection at 230 nm. Three drugs were separated within 7 minutes (Ali et al.,
2011).
A LC-MS (liquid chromatographic tandem mass spectrometric) method was
developed for cefixime analysis in human serum/plasma. The method was performed on a C-
8 column coupled with a mass spectrometer. Water: acetonitrile: formic acid (60:40:0.5,
v/v/v) constituted the mobile phase. This method was linear in range of 0.05-8 µg per ml
(Meng et al., 2005).
Additionally, several HPTLC methods were developed for the simultaneous
determination of cefixime with other drugs in the same dosage form.
In a developed HPTLC-method to estimate cefixime, ceftriaxone and cefotaxime in
drug dosage forms, methanol- ethyl acetate-water-acetone were used as mobile-phase
(2.5:5:1.5:2.5 v/v/v/v) [Jovanovic et al., 1998].
173
An HPTLC procedure was developed and validated to estimate of cefixime and
ofloxacin in Tablets. Methanol-ethyl acetate-ammonia (3.5-3.5-1.5 v/v/v) were used as
mobile phase at 295nm UV detection. Results were linear in range of 50 to 500 ng/band for
both cefixime and ofloxacin (Khandagle et al., 2010).
A validated HPTLC technique described to analyze cefixime and erdosteine in bulk
form and in combined preparations has the mobile phase composing of ethyl acetate, acetone,
methanol and water (7.5: 2.5: 2.5: 1.5) and densitometric determination at 235 nm. The
method was performed on the plates of aluminium which were pre-coated with silica-gel
60F-254. The results were found linear in range of 100-500ng/band and 150-750 ng/band for
cefixime and erdosteine, respectively (Dhoka et al., 2013).
Another HPTLC-method development and validation, to detect ofloxacin and
cefixime simultaneously in Tablets used n-butanol: ammonia: water: DMSO (8:3:1:2,
v/v/v/v) as a mobile phase. This separation was performed on aluminum foil plates percolated
with silica gel 60GF-254. Densitometric detection was performed at 297 nm. Linearity was in
the range of 30-180 ng/spot for both drugs (Rao et al., 2011).
In another described HPTLC-method for simultaneous estimation of ambroxol-
hydrochloride and cefixime-trihydrate, the separation was done on aluminium sheets of the
silica-gel 60-F254 by using methanol: acetonitrile: triethylamine (1: 8.2: 0.8, v/v/v) as a
mobile phase. The method linear in range of 200 to 1000 ng/spot for cefixime and ambroxol,
with densitometric measurements of their spots at 254 nm (Deshpande et al., 2010).
In another published and validated HPTLC densitometric technique for analysis of
ornidazole and cefixime-trihydrate in bulk and in Tablets, the thin layer chromatography
(TLC) aluminium-sheets covered with silica-gel 60 F254 with n-butanol, methanol, toluene,
ammonia 5:2:1:5 (v / v / v / v) were used as a mobile phase. The results were found linear in
the range of 360-840 ng/band for cefixime and 900-2100 ng/band for ornidazole (Devika et
al., 2010).
A high-performance capillary electrophoretic method was also developed for
detection of cefixime and its metabolites (Honda et al., 1992).
An electrophoretic method to determine cefuroxime axetil and cefixime trihydrate in
pharmaceutical dosage forms and in bulk drug was described (Raj, 2010).
174
2.7.2.2 Spectroscopic Analysis of cefixime Formulations:
Different methods have been developed; including high performance liquid
chromatography, liquid chromatography mass spectrometry, voltammetry and capillary
electrophoresis for analysis of cefixime (Azmi et al., 2013).
Certain spectrophotometric methods have been developed to determine cefixime
Tablets using different hydrotropic agents as urea, sodium tartarate, sodium acetate, sodium
citrate and others and then cefixime was determined by conventional spectrophotometric
estimation at 288 nm or by area under curve method, these methods exhibit linearity range of
5-30 µg ml-1 (Maheshwari et al., 2010; Pareek et al., 2010). The role of different hydrotropic
agents in the determination of cefixime by HPTLC method was also studied (Pareek et al.,
2010).
In another study, two spectrophotometric methods were developed to estimate
cefixime and ornidazole simultaneously in Tablet dosage form. The first method is first order
derivative spectroscopy, wavelengths selected for quantification were 311.5 nm for cefixime
and 290 nm for ornidazole. Area under curve (AUC) method is the second method and AUC
in the range of 285-295 nm for cefixime and 307-317 nm for ornidazole were selected for the
analysis (Nanda et al., 2009a,b).
In another publication two methods of spectrophotometry stated for simultaneous
quantification of cefixime and ornidazole in Tablets, first method (Vierodt's method) is based
on simultaneous equations obtained by using mean absorptive values. For analysis selected
wavelengths were 290 nm (ʎmax of cefixime) and 312 nm (ʎmax of ornidazole), respectively, in
methanol. Q-analysis method is the second method which is based on absorbance ratio at two
selected wavelengths 303 nm (iso-absorptive point) and 312 nm (ʎmax of ornidazole) and the
concentration of each component is calculated from specific equations (Nanda et al.,
2009a,b).
Development of two spectrophotometric methods for assay of cefixime and ofloxacin
simultaneously from Tablets, first method involves formation of simultaneous equations at
234-nm (ʎmax of cefixime) and 296nm (ʎmax of ofloxacin). Second method involves formation
of absorbance ratio equation at 275nm (isoabsorptive point) and 296-nm (ʎmax of ofloxacin)
using methanol as a solvent (Dube et al., 2011).
175
A colorimetric procedure for simultaneous determination of cefixime and ofloxacin in
same formulation were developed. Ofloxacin developes a product of orange color in presence
of ferric chloride solution in acidic medium and absorbance of orange colored species formed
was measured at wavelength of 435 nm against reagent blank. Cefixime forms a product of
green color with Fehling-solution and the absorbance of this greenish species formed was
measured at 490-nm wavelength against reagent blank (Kumar et al., 2011).
In a validated spectrofluorimetric method published to analyze cefixime in
pharmaceuticals and in pure forms, the fluorescent product showed maximum fluorescence
intensity at ʎ 378 nm after excitation at ʎ 330 nm. The method was linear in range of 0.02-4
µg per ml (Shah et al., 2011).
A spectrofluorimetric method was studied for analysis of cefixime, cephalexin and
cefotaxime in pharmaceuticals. Method was based on the reaction between cefixime and 1, 2 -
NQS (naphthoquinone-4-sulfonic) at pH 12.0 to give highly fluorescent derivative extracted
with chloroform and then measured at 600 nm after excitation at 520 nm. The method was
linear in range of 10-35 ng ml-1 (Elbashir et al., 2011).
A newer spectrofluorimetry for determination of cefixime and other two
cephalosporins in pharmaceutical formulation was developed. The method based on reaction
between cefixime and HPTS (8-hydroxy-1,3,6-pyrenetrisulfonic acid trisodium salt) at pH
12.0 to give highly fluorescent derivative extracted with chloroform and then measured at
520 nm after excitation at 480nm (Ahmed et al., 2013).
Volummetric methods also have been developed to determine cefixime in dosage
forms and biological fluids (Reddy et al., 2003; Golcu et al., 2005; Jain et al., 2010).
176
CHAPTER III
MATERIALS AND METHODS
Pharmacokinetics and bioequivalence of two brands of cefixime were determined in healthy
adult female and male human subjects. The experimental protocol for the present study is given
below:
3.1 Experimental subject:
Twenty healthy adult human subjects, ten each of either sex, were selected for present study.
Description of experimental subjects has been presented in Table 3.1 and Table 3.2 and record
of their laboratory investigations i.e. blood group, complete blood composition (CBC),
Erythrocyte sedimentation rate (ESR), lipid profile, liver function test (LFT), blood urea and
creatinine, random blood sugar and screening for hepatitis-b and hepatitis-c have been shown in
appendices 1 and 2.
3.1.1 Selection criteria of volunteers:
177
Volunteers were randomly selected and experiments were performed at the Department of
Physiology and Pharmacology, University of Agriculture, Faisalabad. Selection of volunteers
was according to the following criteria:
Volunteers of age between 25 & 35 years were selected.
Weight of all volunteers was recorded.
Height of all volunteers was measured.
Blood pressure, pulse rate and temperature were recorded for all the subjects and were
found in its normal range.
No female volunteer was in period of her menstrual cycle.
Volunteers had no kind of disease or abnormality.
No subject had history or evidence of hepatic, cardiac, respiratory, neurological,
immunological, renal, gastrointestinal or hematological deviations or any acute or
chronic disease.
Clinical examination and necessary laboratory investigations (hematology and
biochemistry) were performed for each individual before selection.
Volunteers had not taken any other medication at least seven days before start of the
experiment.
Each experimental unit had no allergy to cefixime or other beta-lactam antibiotics.
Written consent was taken from each volunteer. All the selected volunteers were
informed about the objective of study, frequency of blood sampling and possible side
effects of the drug which they might face during the study period.
Sr. No. Age
(years)
Height
(meter)
Body weight
(Kg)
Temperature
(Fº)
Blood Pressure
(mmHg)
Systolic Diastolic
1 32 1.73 70 98.6 120 80
2 26 1.7 65 98.0 120 70
3 29 1.65 62 98.6 124 80
178
Table 3.1: Description of 10 healthy adult female volunteers involved during
investigations of pharmacokinetics and bioequivalence of cefixime.
4 28 1.6 60 98.4 110 70
5 25 1.58 58 98.4 120 74
6 27 1.59 59 98.6 120 80
7 30 1.66 64 98.2 118 70
8 31 1.62 61 98.0 120 80
9 33 1.56 56 98.6 110 70
10 29 1.61 60 98.4 120 60
Mean±SE 29±0.82 1.63±0.02 61.50±1.27 98.38±0.08 118.20±1.44 73.40±2.11
Sr. No. Age
(years)
Height
(meter)
Body
weight
(Kg)
Temperature
(Fº)
Blood Pressure
(mmHg)
Systolic Diastolic
1 25 1.82 72 98.6 120 70
2 27 1.9 79 98.6 110 76
3 29 1.78 68 98.4 100 70
4 26 1.8 74 98.6 110 80
5 31 1.75 73 98.0 120 70
6 33 1.73 70 98.2 120 80
179
Table 3.2: Description of 10 healthy adult male volunteers involved during investigations
of pharmacokinetics and bioequivalence of cefixime.
3.2 Medicines:
Two commonly prescribed brands of cefixime were used in present investigations,
one being multinational brand and most expensive in market and the other being national one
and was of the lowest cost.
3.2.1 Multinational brand of cefixime:
Cefspan® 400 mg capsule (Barrett Hodgson Pakistan (Pvt.) Ltd. F/423, Karachi-
75700, Pakistan) Batch number MC-460, Expiry date 06-14, Retail Price Rs.102.50 per
capsule.
3.2.2 National brand of cefixime:
Ceforal-3® 400 mg capsule (Zafa Pharmaceuticals Laboratories (Private) Ltd. L-1/B,
industrial area, Karachi-75950, Pakistan) Batch number 03, Expiry date 04-15, Retail Price
Rs. 32.00 per capsule.
7 27 1.7 67 98.6 120 80
8 29 1.89 81 98.8 110 70
9 28 1.77 75 98.0 100 70
10 30 1.76 71 98.6 120 80
Mean±SE 28.50±0.76 1.79±0.02 73.00±1.41 98.44±0.09 113.00±2.60 74.60±1.58
180
3.3 Experimental design:
Each of cefixime brands was administered orally in 10 healthy adult female and 10
healthy adult male subjects with a wash out period of 7 days between two administrations.
Volunteers might be ambulatory during the study but were prohibited from strenuous activity
on sampling days.
3.3.1 Sample collection:
In each experiment a blank blood sample was collected prior to drug administration. More
blood samples were taken with hourly interval up to 6 hours and then on 12 and 24 hours,
post medication. Samples were collected aseptically in heparinized centrifuge tubes from
forearm vein through IV cannula of 20G needle and then centrifuged at 3000 rpm for 5
minutes for plasma separation. The collected plasma was decanted in polypropylene tubes
and stored frozen at -20°C until assayed.
3.4 Analytical method:
The concentration of cefixime in plasma was measured with a sensitive, selective and
accurate High Performance Liquid Chromatographic (HPLC) method (Alshare, 1999).
3.4.1 Chemicals:
All the chemicals used were of analytical grade. Main chemicals used in HPLC
analysis of cefixime are listed in the following Table 3.3 with their sources.
Table 3.3: Chemicals used for analysis of cefixime by HPLC method.
Sr # Chemical Name Source
1 Cefixime-standard
(As cefixime trihydrate 99%)
Pharmagen Ltd., Lahore, Pakistan
2 Methanol Fisher Scientific Limited, UK
3 Acetonitrile Fisher Scientific Limited, UK
4 Monobasic sodium phosphate Merck Germany
5 Orthophosphoric acid Merck Germany
181
All the above mentioned chemicals were of analytical grade. Cefixime standard (as
cefixime trihydrate, 99%) was a kind gift from the Pharmagen Ltd., Lahore, Pakistan. All the
purchased solvents were HPLC grade. Acetonitrile and methanol were from Fisher Scientific
Limited, UK, and monobasic sodium phosphate and phosphoric acid were from Merck,
Germany.
3.4.2 Instrumentation and chromatographic conditions:
Chromatography was performed with a High Performance Liquid Chromatograph
(Sykam, S-1122) and drug was determined using UV/Visible detector (Sykam, S-3210). The
output of the detector was monitored with computer software (Peak Simple Chromatography
Data System, Buck Scientific Inc., East Norwalk). A stainless steel column packed with
YMC pack A-312 (Thermo Hypersil-Keystone, BDS-C18 with 250 x 4.6 mm dimensions and
5 µm particle size) was used. The column was protected with a pre-column (Guard-Pak™)
filled with a μBondapak™ C18 cartridge (Thermo Hypersil, England). Separation of cefixime
was achieved at 30ºC, using an isocratic mode. The UV detector was set at 275 nm and the
flow rate was 1 ml/min.
3.4.3 Preparation of mobile phase:
The mobile phase was prepared fresh on the day of analysis by combining 170 ml of
acetonitrile, 1.36g of monobasic sodium phosphate, 830 ml of distilled water, and 85%
phosphoric acid for the adjustment of pH up to approximately 2.7, and was filtered and
degassed by vacuum before use.
3.4.4 Cefixime standard solutions:
Stock solution of cefixime was prepared by dissolving 11.4 mg of the compound
(equivalent to l0 mg of cefixime, corrected for purity) in 1.0 ml of HPLC-grade methanol and
the mixture was diluted to 10 ml with distilled water. This stock solution, equivalent to 1.0
mg/ml, was refrigerated at 3°C for up to one week.
Then 1.0 mg/ml of the stock was further diluted 1:10 with distilled water to prepare an
additional standard that was l00 µg/ml.
3.4.5 Plasma calibration standard:
182
Calibration standard for the plasma assay was prepared by adding 100 µl of the 100
µg/ml cefixime stock solution to appropriate volume of drug-free plasma. Plasma cefixime
calibration standard curve was prepared at concentration of 1, 2, 3, 4 and 5 µg/ml.
Chromatograms of the standards of cefixime along with plasma blank are shown in Figs 3.1a-
3.1f and linearity curve has been shown in Fig 3.2. The calibration curve was constructed by
plotting the concentration versus peak area. The curves was linear over the range of 1 to 5 µg/ml
for cefixime (R2 = 0.9986; y = 43.1x+0.5) in human plasma.
3.4.6 Plasma sample preparation:
A 200 µl aliquot of the plasma standard or unknown sample was transferred to a
polypropylene 1.5-ml snap-cap centrifuge tube (Eppendorf, Hamburg, F.R.G) and 200 µ1 of
the methanol was added. The tube was vortexed at high speed for 30 seconds and centrifuged
at 15000 rpm for l0min. The clear supernatant was taken in a fresh disposable syringe and
filtered via syringe filter of 0.45 micron size filter medium.20 µl of the filtered sample was
injected into HPLC for each analysis.
Fig 3.1a: Chromatogram of blank plasma of healthy volunteer.
183
Fig 3.1b: Chromatogram of 1 µg/ml of cefixime standard.
Fig 3.1c: Chromatogram of 2 µg/ml of cefixime standard.
184
Fig 3.1d: Chromatogram of 3 µg/ml of cefixime standard.
Fig 3.1e: Chromatogram of 4 µg/ml of cefixime standard.
185
Fig 3.1f: Chromatogram of 5 µg/ml of cefixime standard.
186
Fig 3.2: Standard curve of cefixime.
3.4.7 Procedure:
Equal volume (20 µl) of the Standard Preparation and the Sample Preparation was
injected separately into the chromatograph. Chromatogram was recorded, and the area for the
major peaks for both was measured.
3.4.8 Quantitation:
Drug concentration in the unknown plasma sample was calculated by interpolation
from the linear least-squares regression line of the multi-level standard curve plot of peak-
height ratio versus cefixime concentration in the calibration standard curve.
3.5 Calculations:
y = 43.222x + 0.051R² = 0.9996
A
r
e
a
Concentration(lm/gµ)
187
Concentration of cefixime versus time data were used for calculating parameters of
pharmacokinetic and bioavailability.
3.5.1 Pharmacokinetic:
Pharmacokinetic calculations were done after one compartment open model with the
computer programme MW/PHARM version 3.02 by F. Rombout, in cooperation with
University Centre for Pharmacy, Department of Pharmacology and Therapeutics, University of
Gronigen & Medi/Ware, copy right 1987-1991. The definitions and/or formulae of kinetic
parameters derived are given in Table 3.4.
Table 3.4: Definitions and/or formulae of kinetic parameters derived.
Kinetics
parameters Units Definitions and/or method of calculation
B µg/ml Extrapolated zero time drug concentration of elimination phase.
Β hr-1 Overall elimination rate constant.
t1/2β hr Biological half life = 0.693/β
Vd l/kg Apparent volume of drug distribution. Vd = Dose/B
ClB l/hr/kg Total body clearance = Vd. β
3.5.2 Bioavailability:
Parameters of bioavailability were calculated by using method as followed by Gibaldi,
(1984).The definitions and/or formulae of bioavailability parameters derived are given in Table
3.5.
Table 3.5: Definitions and/or formulae of bioavailability parameters derived.
188
Kinetics
parameters Units Definitions and/or method of calculation
Cmax µg/ml It is the maximum concentration given by a drug in the plasma.
Tmax hr It is the time at which maximum concentration of drug is obtained in
the plasma.
AUC µg.hr/ml
It is the area under the plasma drug concentration versus time
curve, calculated by trapezoidal rule.
AUC = C.dt
(Where C is the plasma drug concentration at time t)
AUMC µg.hr2/ml
The first moment of a plasma drug concentration time profile is
the area under the curve resulting from plot of the product of time
and drug concentration versus time curve.
AUMC = C.t dt
( Where dt is the time interval and C.t is the product of plasma
drug concentration and time)
MRT hr
Mean residence time is the time required to eliminate 63.2% of the
dose from the body and is determined by the ratio of AUMC and
AUC.
(MRT = AUMC / AUC)
3.5.3 Bioequivalence:
Relative bioavailability of cefixime brands was calculated using method as followed
by Aboulenein et al. (2005). Estimates of extent and rate of absorption comparison in terms
of AUC and Cmax between the test (ceforal-3) and reference (cefspan) brands, respectively,
were calculated to evaluate either the brands are bioequivalent or not. The brands were
considered bioequivalent if the relative bioavailability for rate (Cmax) and extent (AUC) of
absorption were within the predetermined bioequivalence range of 80% to 125%.
189
3.6 Statistical Analysis:
Mean±SE for each concentration and parameter was calculated. Concentration of
cefixime versus time data were used for calculating parameters of pharmacokinetic and
bioavailability. Parameters of bioavailability were calculated by using method as followed by
Gibaldi, (1984). For bioequivalence study, ratio of AUC and Cmax between test and reference
brands was determined. Data was statistically analyzed by applying student’s paired t-test for
significance (P ≤ 0.05). Where necessary, comparison amongst parameters was carried out by
applying DMR conditional to the significance of ANOVA. Statistical analysis was carried out
with PC-program MStat-C by Freed, R.D. and Eisensmith. S.P., Michigan State University,
USA, and the figures were prepared using Microsoft Excel version 2003.
190
CHAPTER IV
RESULTS
Pharmacokinetics and bioequivalence of two brands of cefixime were investigated following a single oral
dose of 400 mg in healthy adult female and male volunteers. The results of plasma concentrations,
pharmacokinetic and bioavailability parameters for brands, cefspan and ceforal-3, of cefixime in female
and male groups are presented below:
4.1 Plasma concentration:
To determine the concentration of cefixime in the plasma, blood samples were taken from 10
healthy female and 10 male volunteers. Each volunteer was orally administered two brands of 400mg
cefixime capsule with a washout period of 7 days and the results are presented in Tables 4.1.1, 4.1.2, 4.1.4
and 4.1.5.
The concentration of cefspan and ceforal-3 at different time intervals after oral administration in
individual groups of female and male volunteers has been presented in Table and Fig 4.1.1 for cefspan in
females, Table and Fig 4.1.2 for cefspan in males, Table and Fig 4.1.4 for ceforal-3 in females and Table
and Fig 4.1.5 for ceforal-3 in males. Gender differences (Table and Fig 4.1.3, Table and Fig 4.1.6) and
brand differences (Table and Fig 4.1.7, Table and Fig 4.1.8) in plasma concentrations have been
compared by t-test and these results are also shown in their respective Tables. The statistical comparison
of mean±SE values of these concentrations amongst brands in male and male genders was carried out
with DMR test when ANOVA was significant (Table and Fig 4.1.9).
4.1.1 Plasma concentrations of cefspan
4.1.1.1 Female subjects:
From Table 4.1.1 it has been found that the mean±SE plasma concentration of orally
administered cefspan reached its maximum from 0.78±0.15 µg/ml at 1 hr to3.03±0.45 at 3hr and then
declined in a progressive fashion with passage of time to 0.19±0.04µg/ml at 24 hr. The mean±SE values
for cefspan concentration in plasma of10 healthy adult females have been plotted against time in Fig
4.1.1. Plasma concentration trend shows that it reached to maximum in 3 hours after drug administration
and declined progressively with passage of time.
4.1.1.2 Male subjects:
191
The values for the plasma concentration of cefspan in 10 healthy adult male subjects have been
shown in Table 4.1.2. The mean±SE concentration was 1.26±0.12 µg/ml at 1 hr after oral dose of cefspan
which reached maximum to 4.05±0.42 µg/ml at 4 hr and declined over time to 0.33±0.05 µg/ml at 24 hr.
The means±SE values for plasma concentration of cefspan in 10 males have been plotted in Fig 4.1.2
against time after oral dose. Like previous group, after maximum absorption plasma concentration
declined slowly.
4.1.1.3 Gender variation:
A statistical appraisal of gender differences in mean±SE plasma concentrations of cefspan in
females and males has been shown in Table 4.1.3 and Fig 4.1.3 indicating significant (P < 0.05) gender
differences only at 1 and 5 hours after drug administration.
192
Table 4.1.1: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral administration 400 mg in 10 healthy adult female subjects.
Subject
No.
Time after administration (hours)
1 2 3 4 5 6 12 24
1 0.77 3.05 5.12 3.71 2.58 2.46 1.27 0.21
2 1.99 2.02 4.06 3.19 3.08 1.57 1.08 0.38
3 0.42 1.55 2.11 2.32 2.09 1.03 0.47 0.15
4 0.54 0.92 2.18 2.23 1.46 1.34 0.49 0.28
5 0.56 2.75 3.99 4.53 2.25 1.59 0.87 0.01
6 0.82 0.92 1.17 3.24 1.62 2.21 0.70 0.19
7 0.33 0.94 4.41 1.71 1.81 1.76 0.82 0.26
8 0.77 1.06 1.22 2.14 2.51 2.09 0.99 0.07
9 1.10 2.23 3.97 2.93 2.32 2.30 1.95 0.01
10 0.47 1.53 2.07 3.73 2.49 1.62 1.38 0.31
Mean±SE 0.78±0.15 1.69±0.25 3.03±0.45 2.97±0.28 2.22±0.15 1.79±0.14 1.00±0.14 0.19±0.04
193
194
Fig 4.1.1: Mean±SE plasma concentrations (µg/ml) of cefspan on a semi logarithmic scale versus time following a single oral administration 400 mg in
10 healthy adult female subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
195
Table 4.1.2: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral administration 400 mg in 10 healthy adult male subjects.
Subject
No.
Time after administration (hours)
1 2 3 4 5 6 12 24
1 1.27 1.74 2.09 2.75 2.14 1.97 1.19 0.39
2 1.69 1.76 3.45 5.21 4.74 2.49 1.71 0.33
3 1.64 3.29 4.34 4.58 5.82 6.62 1.13 0.42
4 1.57 1.69 2.44 2.69 2.91 2.72 1.53 0.56
5 1.19 2.35 3.43 3.12 2.04 1.99 1.10 0.21
6 0.82 2.02 3.31 6.10 5.56 2.04 1.64 0.39
7 0.87 1.13 2.82 2.77 1.97 1.55 0.82 0.07
8 1.78 2.04 6.15 3.36 3.09 2.18 1.46 0.38
9 0.91 1.41 2.18 4.04 2.09 1.43 0.73 0.45
10 0.87 2.77 3.24 5.89 6.83 4.04 0.63 0.07
Mean±SE 1.26±0.12 2.02±0.20 3.35±0.38 4.05±0.42 3.72±0.58 2.70±0.49 1.19±0.12 0.33±0.05
196
197
Fig 4.1.2: Mean±SE plasma concentrations (µg/ml) of cefspan on a semi logarithmic scale versus time following a single oral administration 400 mg in
10 healthy adult male subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
198
Table 4.1.3: Mean±SE plasma concentrations (µg/ml) of cefspan following a single oral
administration 400 mg in healthy adult female and male subjects.
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
Time (hours) Female Male
1 0.78±0.15* 1.26±0.12
2 1.69±0.25 NS 2.02±0.20
3 3.03±0.45 NS 3.35±0.38
4 2.97±0.28 NS 4.05±0.42
5 2.22±0.15* 3.72±0.58
6 1.79±0.14 NS 2.70±0.49
12 1.00±0.45 NS 1.19±0.12
24 0.19±0.04 NS 0.33±0.05
199
Fig 4.1.3: Mean±SE plasma concentrations (µg/ml) of cefspan on a semi logarithmic scale versus time following a single oral administration 400 mg in
healthy adult female and male subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
Female Male
200
Table 4.1.4: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral administration 400 mg in 10 healthy adult female subjects.
Subject
No.
Time after administration (hours)
1 2 3 4 5 6 12 24
1 0.35 0.56 1.85 3.45 4.58 2.86 0.68 0.03
2 0.68 2.37 3.00 3.83 2.69 1.88 0.77 0.07
3 1.22 1.36 1.81 2.81 2.23 2.09 0.89 0.01
4 0.56 1.85 2.82 1.99 1.85 1.06 0.63 0.08
5 1.34 2.04 3.33 5.12 2.07 1.71 0.94 0.05
6 0.59 1.69 4.62 2.30 2.21 1.41 0.56 0.03
7 0.42 1.43 2.63 3.64 2.69 1.97 0.89 0.12
8 0.63 1.55 1.64 2.30 1.48 1.31 0.68 0.19
9 0.42 0.66 2.14 2.98 2.69 1.74 0.56 0.23
10 0.61 0.79 1.38 2.28 2.39 2.82 0.68 0.33
201
Mean±SE 0.68±0.11 1.43±0.19 2.52±0.31 3.07±0.30 2.49±0.26 1.89±0.19 0.73±0.04 0.11±0.03
202
Fig 4.1.4: Mean±SE plasma concentrations (µg/ml) of ceforal-3 on a semi logarithmic scale versus time following a single oral administration 400 mg
in 10 healthy adult female subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
203
Table 4.1.5: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral administration 400 mg in 10 healthy adult male subjects.
Subject
No.
Time after administration (hours)
1 2 3 4 5 6 12 24
1 0.89 2.30 2.72 2.35 1.67 1.59 0.94 0.42
2 0.66 1.31 3.70 3.97 3.49 2.23 0.94 0.21
3 0.61 1.03 3.26 2.58 2.28 2.11 0.59 0.11
4 0.63 1.97 3.00 2.86 1.55 1.50 1.01 0.42
5 0.89 2.30 3.17 6.90 6.36 5.52 2.42 0.45
6 0.63 1.53 1.74 1.53 1.29 0.85 0.33 0.04
7 1.01 2.68 2.89 1.53 1.48 1.27 0.87 0.38
8 1.08 1.57 2.28 3.89 2.42 2.18 1.50 0.03
9 1.17 2.07 2.21 3.22 2.42 1.90 1.36 0.24
10 1.74 2.79 3.92 5.89 6.40 3.71 2.39 0.56
204
Mean±SE 0.93±0.11 1.96±0.18 2.89±0.21 3.47±0.56 2.94±0.61 2.29±0.43 1.24±0.22 0.28±0.06
205
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
206
Fig 4.1.5: Mean±SE plasma concentrations (µg/ml) of ceforal-3 on a semi logarithmic scale versus time following a single oral administration 400 mg
in 10 healthy adult male subjects.
207
Table 4.1.6: Mean±SE plasma concentrations (µg/ml) of ceforal-3 following a single oral
administration 400 mg in healthy adult female and male subjects.
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
Time (hours) Female Male
1 0.68±0.11 NS 0.93±0.11
2 1.43±0.19 NS 1.96±0.18
3 2.52±0.31 NS 2.89±0.21
4 3.07±0.30 NS 3.47±0.56
5 2.49±0.26 NS 2.94±0.61
6 1.89±0.19 NS 2.29±0.43
12 0.73±0.04* 1.24±0.22
24 0.11±0.03* 0.28±0.06
208
209
Fig 4.1.6: Mean±SE plasma concentrations (µg/ml) of ceforal-3 on a semi logarithmic scale versus time following a single oral administration 400 mg
in healthy adult female and male subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
Female Male
210
Table 4.1.7: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 following a single
oral administration 400 mg in healthy adult female subjects.
NS: Non-significantly (P > 0.05) different from the respective value.
Time (hours) Cefspan Ceforal-3
1 0.78±0.15 NS 0.68±0.11
2 1.69±0.25 NS 1.43±0.19
3 3.03±0.45 NS 2.52±0.31
4 2.97±0.28 NS 3.07±0.30
5 2.22±0.15 NS 2.49±0.26
6 1.79±0.14 NS 1.89±0.19
12 1.00±0.14 NS 0.73±0.04
24 0.19±0.04 NS 0.11±0.03
211
Fig 4.1.7: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 on a semi logarithmic scale versus time following a single oral
administration 400 mg in healthy adult female subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
Cefspan Ceforal-3
212
Table 4.1.8: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 following a single
oral administration 400 mg in healthy adult male subjects.
NS: Non-significantly (P > 0.05) different from the respective value.
Time (hours) Cefspan Ceforal-3
1 1.26±0.12 NS 0.93±0.11
2 2.02±0.20 NS 1.96±0.18
3 3.35±0.38 NS 2.89±0.21
4 4.05±0.42 NS 3.47±0.56
5 3.72±0.58 NS 2.94±0.61
6 2.70±0.49 NS 2.29±0.43
12 1.19±0.12 NS 1.24±0.22
24 0.33±0.05 NS 0.28±0.06
213
214
Fig 4.1.8: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 on a semi logarithmic scale versus time following a single oral
administration 400 mg in healthy adult male subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
Cefspan Ceforal-3
215
Table 4.1.9: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 following a single
oral administration 400 mg in healthy adult female and male subjects.
Mean values followed by different letters in a row indicate statistically significant (P < 0.05)
difference.
Time (hours) Female Male
Cefspan Ceforal-3 Cefspan Ceforal-3
1 0.78±0.15 B 0.68±0.11 B 1.26±0.12 A 0.93±0.11 AB
2 1.69±0.25 A 1.43±0.19 A 2.02±0.20 A 1.96±0.18 A
3 3.03±0.45 A 2.52±0.31 A 3.35±0.38 A 2.89±0.21 A
4 2.97±0.28 A 3.07±0.30 A 4.05±0.42 A 3.47±0.56 A
5 2.22±0.15 B 2.49±0.26 AB 3.72±0.58 A 2.94±0.61 AB
6 1.79±0.14 A 1.89±0.19 A 2.70±0.49 A 2.29±0.43 A
12 1.00±0.14 AB 0.73±0.04 B 1.19±0.12 A 1.24±0.22 A
24 0.19±0.04 AB 0.11±0.03 B 0.33±0.05 A 0.28±0.06 A
216
217
Fig 4.1.9: Mean±SE plasma concentrations (µg/ml) of cefspan and ceforal-3 on a semi logarithmic scale versus time following a single oral
administration 400 mg in healthy adult female and male subjects.
0.1
1
10
0 4 8 12 16 20 24
Co
nc
en
trati
on
(μ
g/m
l)
Time (hours)
Female (Cefspan)
Female (Ceforal-3)
Male (Cefspan)
Male (Ceforal-3)
218
4.1.2 Plasma concentrations of ceforal-3:
4.1.2.1 Female subjects:
The plasma concentration values of ceforal-3 given orally in 10 healthy adult female subjects
have been shown in Table 4.1.4 and presented graphically on a scale against time in Fig 4.1.4. The
mean±SE concentration of ceforal-3 was 0.68±0.11 µg/ml at 1hrwhich reached maximum to 3.07±0.30
µg/ml at 4 hr and then declined to 0.11±0.03 µg/ml at 24 hr after oral administration. After reaching its
maximum, the plasma concentration started to fall slowly until the last sample.
4.1.2.2 Male subjects:
The plasma concentrations ofceforal-3 after oral administration in 10 healthy adult males has
been shown in Table 4.1.5. The mean±SE concentration of ceforal-3 at 1hr after oral dose was
0.93±0.11µg/ml reaching its maximum to 3.47±0.56 µg/ml at 4 hr and then decreased to 0.28±0.06 µg/ml
at 24 hours after dose given orally. The mean±SE values for plasma concentration of ceforal-3 after oral
administration in 10males have been plotted on a semi-logarithmic scale against time in Fig 4.1.5. The
plasma concentration revealed a monophasic progressive decline.
4.1.2.3 Gender variation:
Gender differences in the mean±SE plasma concentrations of ceforal-3 in both gender groups are
shown in Table 4.1.6 indicating gender differences (P < 0.05) at 12 and 24 hrs, post medication.
4.1.3. Plasma concentrations of cefspan and ceforal-3:
4.1.3.1 Brand variation in female subjects:
A statistical appraisal of brand differences in mean±SE plasma concentrations of cefspan and
ceforal-3 in females has been shown in Table 4.1.7 and Fig 4.1.7. No significant (P < 0.05) difference
between both brands was observed when administered in females.
4.1.3.2 Brand variation in male subjects:
Brand differences in mean±SE plasma concentrations of cefspan and ceforal-3 in males are
shown in Table 4.1.8 and Fig 4.1.8. Both brands showed non significant (P ˃0.05) difference at any time
after dosing in males.
4.1.3.3 Brand variation in female and male Genders:
A further comparison of the mean±SE values for plasma concentrations of both brands, cefspan
and ceforal-3 in male and female genders, presented in Table 4.1.9 and Fig 4.1.9,showed that cefspan in
219
males had highest, cefspan in females andceforal-3 in males intermediate and ceforal-3 in females
showed lower plasma concentrations at most of the times after oral administration.
4.2 Pharmacokinetics:
Pharmacokinetics of two brands, cefspan and ceforal-3, of cefixime was determined in healthy
adult female and male subjects following oral administration of a single dose of 400 mg capsule.
Pharmacokinetic analysis was carried out by one compartment open model.
The results showing pharmacokinetic parameters (B, β, t1/2β, Vd and ClB) of cefspan and ceforal-3
administered in healthy adult female and male groups are given in Tables 4.2.1, 4.2.2, 4.2.4 and 4.2.5,
respectively. Comparison of mean±SE results of various pharmacokinetic parameters in 10 females and
10 males of each group are shown in Table 4.2.3 and Table 4.2.6, while, cefspan has been compared with
ceforal-3 in Table 4.2.7 and Table 4.2.8, respectively, with help of t-test. The statistical comparison of
mean±SE values of pharmacokinetic parameters of cefspan and ceforal-3 in females and males was
carried out by computing ANOVA and then applying DMR test (Table 4.2.9).
4.2.1 Pharmacokinetics of cefspan:
4.2.1.1 Female subjects:
Mean±SE results of various parameters for pharmacokinetic of cefspan in 10 healthy adult
female subjects are shown in Table 4.2.1. It can be seen from the Table 4.2.1 that mean±SE values of
pharmacokinetic parameters; extrapolated zero time concentration (B) 5.14±0.74 µg/ml, elimination
rate constant (β) 0.21±0.03 hr-1, elimination half life (t1/2β) 3.99±0.54 hr, volume of distribution (Vd)
1.38±0.22 l/kg and total body clearance (ClB) 0.27±0.02 l/hr/kg, respectively, have been determined in
10 healthy adult female subjects following administration of cefspan 400 mg.
4.2.1.2 Male subjects:
The mean±SE values for the pharmacokinetic parameters of cefspan in males are presented in
Table 4.2.2. The mean±SE values of pharmacokinetic parameters for B, β and t1/2ß in males were
5.94±0.78 µg/ml, 0.16±0.02hrs-1and 5.01±0.61 hours, respectively. Mean±SE value for Vd was 1.09±0.15
l/kg and that of ClB was 0.16±0.02 l/hr/kg.
4.2.1.3 Gender variation:
Gender difference between pharmacokinetic parameters (mean±SE) of cefspan has been shown
in Table 4.2.3. Results showed that all the pharmacokinetic parameters of both genders were non-
significantly (P > 0.05) different except that of total body clearance (P < 0.05).
220
Table 4.2.1: Mean±SE pharmacokinetic parameters of cefspan following a single oral
administration 400 mg in 10 healthy adult female subjects.
Subject No. B β t1/2β Vd ClB
(µg/ml) (hr-1) (hr) (l/kg) (l/hr/kg)
1 7.16 0.20 3.52 0.80 0.16
2 3.38 0.11 6.62 0.62 0.17
3 2.74 0.15 4.78 2.35 0.34
4 2.22 0.10 6.69 2.69 0.28
5 7.36 0.36 1.94 0.94 0.33
6 3.67 0.16 4.34 1.85 0.29
7 4.68 0.18 3.76 1.34 0.26
8 4.84 0.24 2.88 1.36 0.33
9 9.59 0.44 1.59 0.73 0.32
10 5.77 0.18 3.83 1.16 0.21
Mean±SE 5.14±0.74 0.21±0.03 3.99±0.54 1.38±0.22 0.27±0.02
221
Table 4.2.2: Mean±SE pharmacokinetic parameters of cefspan following a single oral
administration 400 mg in 10 healthy adult male subjects.
Subject No. B β t1/2β Vd ClB
(µg/ml) (hr-1) (hr) (l/kg) (l/hr/kg)
1 3.31 0.10 7.02 1.68 0.17
2 7.89 0.17 3.99 0.64 0.11
3 8.25 0.15 4.54 0.71 0.11
4 4.02 0.09 7.49 1.34 0.12
5 4.35 0.14 4.87 1.26 0.18
6 8.85 0.19 3.56 0.65 0.13
7 5.41 0.25 2.73 1.23 0.31
8 4.94 0.12 5.86 1.00 0.12
9 2.82 0.09 7.66 1.89 0.17
10 9.59 0.29 2.43 0.59 0.17
222
Mean±SE 5.94±0.78 0.16±0.02 5.01±0.61 1.09±0.15 0.16±0.02
223
Table 4.2.3: Mean±SE pharmacokinetic parameters of cefspan following a single oral administration 400 mg in healthy adult female and male subjects.
Parameters Units Female
Male
B
µg/ml 5.14±0.74 NS 5.94±0.78
β
hr-1 0.21±0.03 NS 0.16±0.02
t1/2β
hr 3.99±0.54 NS 5.01±0.61
Vd
l/kg 1.38±0.22 NS 1.10±0.15
ClB
l/hr/kg 0.27±0.02* 0.16±0.02
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
224
Table 4.2.4: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral
administration 400 mg in 10 healthy adult female subjects.
Subject No. B β t1/2β Vd ClB
(µg/ml) (hr-1) (hr) (l/kg) (l/hr/kg)
1 4.83 0.27 2.54 1.18 0.32
2 8.50 0.46 1.51 0.72 0.33
3 6.33 0.35 1.99 1.02 0.35
4 3.63 0.19 3.59 1.84 0.35
5 7.54 0.29 2.41 0.78 0.22
6 5.62 0.29 2.34 1.21 0.36
7 5.56 0.23 3.06 1.12 0.25
8 2.66 0.13 5.46 2.47 0.31
9 4.46 0.19 3.62 1.57 0.30
10 4.00 0.15 4.69 1.67 0.25
Mean±SE 5.31±0.57 0.25±0.03 3.12±0.39 1.36±0.17 0.31±0.02
225
Table 4.2.5: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral
administration 400 mg in 10 healthy adult male subjects.
Subject No. B β t1/2β Vd ClB
(µg/ml) (hr-1) (hr) (l/kg) (l/hr/kg)
1 2.77 0.09 7.21 2.01 0.18
2 6.74 0.21 3.24 0.75 0.16
3 5.21 0.23 2.96 1.32 0.31
4 2.97 0.09 7.37 1.82 0.17
5 11.21 0.19 3.63 0.49 0.09
6 4.06 0.37 1.87 1.41 0.52
7 2.36 0.08 8.36 2.54 0.21
8 6.97 0.29 2.37 0.71 0.21
9 4.76 0.15 4.67 1.12 0.17
10 7.46 0.13 5.51 0.76 0.10
Mean±SE 5.45±0.86 0.18±0.03 4.72±0.72 1.29±0.21 0.21±0.04
226
227
Table 4.2.6: Mean±SE pharmacokinetic parameters of ceforal-3 following a single oral administration 400 mg in healthy adult female and male subjects.
Parameters Units Female
Male
B
µg/ml 5.31±0.57 NS 5.45±0.86
β
hr-1 0.25±0.03 NS 0.18±0.03
t1/2β
hr 3.12±0.39 NS 4.72±0.72
Vd
l/kg 1.36±0.17 NS 1.29±0.21
ClB
l/hr/kg 0.31±0.02* 0.21±0.04
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
228
Table 4.2.7: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female
subjects.
Parameters Units Cefspan
Ceforal-3
B
µg/ml 5.14±0.74 NS 5.31±0.57
β
hr-1 0.21±0.03 NS 0.25±0.03
t1/2β
hr 3.99±0.54 NS 3.12±0.39
229
Vd
l/kg 1.38±0.22 NS 1.36±0.17
ClB
l/hr/kg 0.27±0.02 NS 0.31±0.02
NS: Non-significantly (P > 0.05) different from the respective value.
Table 4.2.8: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult male subjects.
Parameters Units Cefspan
Ceforal-3
B
5.94±0.78 NS 5.45±0.86
230
µg/ml
β
hr-1 0.16±0.02 NS 0.18±0.03
t1/2β
hr 5.01±0.61 NS 4.72±0.72
Vd
l/kg 1.10±0.15 NS 1.29±0.21
ClB
l/hr/kg 0.16±0.02 NS 0.21±0.04
NS: Non-significantly (P > 0.05) different from the respective value.
231
Table 4.2.9: Mean±SE pharmacokinetic parameters of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female and
male subjects.
Parameters
Units
Female Male
Cefspan Ceforal-3 Cefspan Ceforal-3
B
µg/ml 5.14±0.74 A 5.31±0.57 A 5.94±0.78 A 5.45±0.86 A
β
hr-1 0.21±0.03 AB 0.25±0.03 A 0.16±0.02 B 0.18±0.03 AB
t1/2β
hr 3.99±0.54 AB 3.12±0.39 B 5.01±0.61 A 4.72±0.72 AB
Vd
l/kg 1.38±0.22 A 1.36±0.17 A 1.10±0.15 A 1.29±0.21 A
232
ClB
l/hr/kg 0.27±0.02 AB 0.31±0.02 A 0.16±0.02 C 0.21±0.04 BC
Mean values followed by different letters in a row indicate statistically significant (P < 0.05) difference.
161
4.2.2 Pharmacokinetics of ceforal-3:
4.2.2.1 Female subjects:
The values for pharmacokinetic parameters (mean±SE) of ceforal-3 in 10females are presented in
Table 4.2.4. The mean±SE value of extrapolated zero hour drug concentration (B) observed in females
was 5.31±0.57 µg/ml and that of β was 0.88±0.09 hours-1. The t1/2ß, mean±SE value, was3.12±0.39 hr.
The mean±SE values for Vd and ClBwere1.36±0.17 l/kg and0.31±0.02 l/hr/kg, respectively.
4.2.2.2 Male subjects:
Pharmacokinetic parameters (mean±SE) of ceforal-3 in males are shown in Table 4.2.5.
Mean±SE values of the B, β, t1/2ß, Vd and ClB were 5.45±0.86 µg/ml, 0.18±0.03 hours-1, 4.72±0.72hr,
1.29±0.21 l/kg and0.21±0.04 l/hr/kg, respectively.
4.2.2.3 Gender variation:
Gender variation for pharmacokinetics values (mean±SE) of ceforal-3 administered in healthy
female and male subjects has been presented in Table 4.2.6. Total body clearance was significantly (P <
0.05) higher in females than in males while, all the remaining pharmacokinetic parameters remained non-
significantly (P > 0.05) different.
4.2.3 Pharmacokinetics of cefspan and ceforal-3:
4.2.3.1 Brand variation in female subjects:
Brand difference amongst pharmacokinetic parameters (mean±SE values) in females has been
shown in Table 4.2.7. Data showed non-significant (P > 0.05) results for all the pharmacokinetic
parameters of cefspan and ceforal-3 administered in female volunteers.
4.2.3.2 Brand variation in male subjects:
Table 4.2.8 represents the brand variation for pharmacokinetic parameters of cefspan and ceforal-
3 in males. All the pharmacokinetic values were non-significantly (P > 0.05) different for cefspan and
ceforal-3 given in healthy males.
4.2.3.3 Gender variation of cefspan and ceforal-3:
Table 4.2.9 showed that the mean±SE values of B were statistically similar (P > 0.05) for both
brands administered in females and males. Non significant (P > 0.05) gender variations were noted in the
mean values of elimination rate (ß) except that of cefspan in males and ceforal-3 in females (P < 0.05).
However, lowest mean value of ß was seen for cefspan in males (0.16±0.02 hr-1), intermediate for ceforal-
3 in males and cefspan in males (0.18±0.03 hr-1 and 0.21±0.03 hr-1) and highest for ceforal-3 in females
162
(0.25±0.03 hr-1). Similar statistical appraisal was noted for half life values of cefspan and ceforal-3 in both
genders. The mean±SE value of half life for cefspan in males (3.99±0.54 hours) and ceforal-3 in females
(4.72±0.72 hours) were significantly (P < 0.05) different. Nevertheless, the longest half life was recorded
for cefspan in males (5.01±0.61 hours) and shortest for ceforal-3 in females (3.12±0.39 hours).The mean
value of Vd for cefspan and ceforal-3 in females and males was found non significantly (P > 0.05)
different. Statistical significant (P < 0.05) gender variation was recorded in the mean±SE values of ClB for
cefspan and ceforal-3 in males and females, respectively, and also between ceforal-3 in females and
males. The highest mean value of ClB was seen for ceforal-3 in females (0.31±0.02 l/hr/kg), intermediate
for ceforal-3 in males and for cefspan in females (0.21±0.04 l/hr/kg and 0.27±0.02 l/hr/kg) and that of the
lowest one for cefspan in males (0.16±0.02 l/hr/kg).
4.3 Bioavailability
In present study, blood samples from 10 females and 10 males were collected after administration
of cefspan and ceforal-3 to each group followed by a wash out period of 7 days. Bioavailability
parameters (Cmax, Tmax, AUC, AUMC and MRT) were calculated for each brand in each group of gender.
The results of bioavailability of each brand in each group of gender have been shown separately
in Tables 4.3.1, 4.3.2, 4.3.4 and 4.3.5, respectively. Bioavailability parameters in female group have been
compared with male group by applying t-test in Table 4.3.3 and Table 4.3.6. Similarly cefspan was
compared with ceforal-3 using t-test in Table 4.3.7 and Table 4.3.8. A statistical comparison of
bioavailability parameters of two brands of cefixime in both genders was computed by applying ANOVA
and DMR test (Table 4.3.9).
4.3.1 Bioavailability of cefspan:
4.3.1.1 Female subjects:
As shown in Table 4.3.1, after oral administration of 400 mg cefspan capsule in female
volunteers, the mean±SE of maximum concentration (Cmax), 2.24±0.23 µg/ml, was achieved at the peak
concentration time (Tmax) of 4.05±0.35 hr with area under time versus concentration curve (AUC) of
27.12±2.25 µg.hr/ml and Area under first moment curve (AUMC) of 208.99±18.47 µg.hr2/ml as the
mean±SE values. Mean±SE residence time (MRT) observed was 7.69±0.20 hr.
4.3.1.2 Male subjects:
As given in Table 4.3.2, maximum concentration (2.93±0.24 µg/ml) of cefspan administered in
males was achieved at 4.11±0.16 hr, as mean±SE. Average area under the plasma concentration-time
curve (AUC) was observed 36.58±3.10 (mean±SE) µg.hr/ml. The mean±SE AUMC and MRT values
were 282.95±23.11 µg.hr2/ml and 7.79±0.28 hr, respectively.
163
4.3.1.3 Gender variation:
Table 4.3.3 represents the gender difference for cefspan. It can be seen that mean±SE values of
AUC in females (27.12±2.25 µg.hr/ml) was significantly (P < 0.05) different than its respective value
(36.58±3.10 µg.hr/ml) in males. Other bioavailability parameters i.e. Cmax, Tmax, AUMC and MRT in
female and male subjects remained non significantly (P > 0.05) different from their respective values.
164
Table 4.3.1: Mean±SE parameters for bioavailability of cefspan following a single oral
administration 400 mg in 10 adult healthy female subjects.
Subject No. Cmax Tmax AUC
(µg.hr/ml)
AUMC
(µg.hr2/ml)
MRT
(µg/ml) (hr) (hr)
1
3.01
4.39 36.53 269.00 7.375
2
2.81
2.88 31.84 250.70 7.88
3
1.53
4.01 17.23 123.60 7.17
4
1.43
4.25 18.11 146.50 8.09
5
2.71
2.80 27.52 175.90 6.39
165
6
1.72
4.75 22.95 176.60 7.69
7
1.72
5.43 24.30 194.30 7.99
8
1.78
4.15 24.35 188.60 7.75
9
3.53
2.30 38.16 299.90 7.86
10
2.12
5.53 30.24 264.80 8.76
Mean±SE
2.24±0.23
4.05±0.35 27.12±2.25 208.99±18.47 7.69±0.20
Table 4.3.2: Mean±SE parameters for bioavailability of cefspan following a single oral
administration 400 mg in 10 adult healthy male subjects.
Subject
No.
Cmax Tmax AUC AUMC MRT
(µg/ml) (hr) (µg.hr/ml) (µg.hr2/ml) (hr)
29.94 258.80 8.64
166
1 2.23 3.98
2
3.50
4.68 42.94 344.60 8.03
3
4.35
4.18 55.63 390.20 7.03
4
2.66
4.47 37.95 340.60 8.97
5
2.58
3.69 30.26 229.70 7.59
6
3.25
5.14 42.05 343.10 8.16
7
1.99
3.93 22.79 163.70 7.19
8
3.23
3.59 39.47 311.40 7.89
9
1.97
3.95 24.91 210.60 8.45
10
3.52
3.51 39.83 236.80 5.95
Mean±SE
2.93±0.24
4.11±0.16 36.58±3.10 282.95±23.11 7.79±0.28
167
Table 4.3.3: Mean±SE parameters for bioavailability of cefspan following a single oral administration 400 mg in healthy adult female and male subjects.
Parameters
Units
Female
Male
Cmax
µg/ml 2.24±0.23 NS 2.93±0.24
Tmax
hr 4.05±0.35 NS 4.11±0.16
AUC
µg.hr/ml 27.12±2.25* 36.58±3.10
AUMC
µg.hr2/ml 208.99±18.47 NS 282.95±23.11
MRT
hr 7.69±0.20 NS 7.79±0.28
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
168
Table 4.3.4: Mean±SE parameters for bioavailability of ceforal-3 following a single oral
administration 400 mg in 10 adult healthy female subjects.
Subject
No.
Cmax Tmax AUC AUMC MRT
(µg/ml) (hr) (µg.hr/ml) (µg.hr2/ml) (hr)
1
1.78
3.67 27.1 181.50 6.69
2
3.13
2.19 26.08 165.90 6.36
3
2.33
2.87 24.8 172.90 6.97
4
1.74
3.81 18.93 131.80 6.96
5
2.78
3.48 28.65 190.90 6.66
6
2.07
3.38 21.57 132.60 6.15
7
2.05
4.42 26.44 193.90 7.34
8
1.59
4.05 19.45 153.60 7.89
9
1.64
5.23 21.4 163.70 7.65
169
10
1.75
5.61 25.42 207.60 8.17
Mean±SE
2.08±0.16
3.87±0.32 23.99±1.07 169.44±7.99 7.09±0.21
Table 4.3.5: Mean±SE parameters for bioavailability of ceforal-3 following a single oral
administration 400 mg in 10 adult healthy male subjects.
Subject
No.
Cmax Tmax AUC AUMC MRT
(µg/ml) (hr) (µg.hr/ml) (µg.hr2/ml) (hr)
1
2.02
3.59 26.48 226.80 8.57
2
2.48
4.67 30.66 226.30 7.38
3
1.93
4.25 23.12 158.00 6.84
4
1.97
4.35 26.87 233.80 8.70
63.42 516.50 8.14
170
5 4.12 5.24
6
1.49
2.70 12.69 75.55 5.95
7
1.87
2.77 24.15 203.90 8.45
8
2.56
3.42 32.55 250.80 7.71
9
2.49
4.38 31.42 258.30 8.22
10
4.44
4.12 58.6 491.30 8.39
Mean±SE
2.54±0.31
3.95±0.26 32.99±5.01 264.13±43.42 7.83±0.28
171
Table 4.3.6: Mean±SE parameters for bioavailability of ceforal-3 following a single oral administration 400 mg in healthy adult female and male subjects.
Parameters
Units Female
Male
Cmax
µg/ml 2.08±0.16 NS 2.53±0.31
Tmax
hr 3.87±0.32 NS 3.95±0.26
AUC
µg.hr/ml 23.99±1.07* 32.99±5.01
AUMC
µg.hr2/ml 169.44±7.99 * 264.13±43.42
MRT
hr 7.09±0.21 NS 7.83±0.28
*: Significantly (P < 0.05) different from the respective value.
NS: Non-significantly (P > 0.05) different from the respective value.
172
Table 4.3.7: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female
subjects.
Parameters
Units Cefspan
Ceforal-3
Cmax
µg/ml 2.24±0.23 NS 2.08±0.16
Tmax
hr 4.05±0.35 NS 3.87±0.32
AUC
µg.hr/ml 27.12±2.25 NS 23.99±1.07
173
NS: Non-significantly (P > 0.05) different from the respective value.
Table 4.3.8: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult male
subjects.
AUMC
µg.hr2/ml 208.99±18.47 NS 169.44±7.99
MRT
hr 7.69±0.20 NS 7.09±0.21
Parameters Units Cefspan
Ceforal-3
174
NS: Non-significantly (P > 0.05) different from the respective value.
Cmax
µg/ml 2.93±0.24 NS 2.53±0.31
Tmax
hr 4.11±0.16 NS 3.95±0.26
AUC
µg.hr/ml 36.58±3.10 NS 32.99±5.01
AUMC
µg.hr2/ml 282.95±23.11 NS 264.13±43.42
MRT
hr 7.79±0.28 NS 7.83±0.28
175
Table 4.3.9: Mean±SE parameters for bioavailability of cefspan and ceforal-3 following a single oral administration 400 mg in healthy adult female and
male.
Parameter Units
Female Male
Cefspan Ceforal-3 Cefspan Ceforal-3
Cmax
µg/ml 2.24±0.23 AB 2.08±0.16 B 2.93±0.24 A 2.53±0.31 AB
Tmax
hr 4.05±0.35 A 3.87±0.32 A 4.11±0.16 A 3.95±0.26 A
AUC
µg.hr/ml 27.12±2.25 BC 23.99±1.07 C 36.58±3.10 A 32.99±5.01 AB
AUMC
µg.hr2/ml 208.99±18.47 AB 169.44±7.99 B 282.95±23.11 A 264.13±43.42 A
176
Mean values followed by different letters in a row indicate statistically significant (P < 0.05) difference.
MRT
hr 7.69±0.20 A 7.09±0.21 A 7.79±0.28 A 7.83±0.28 A
177
4.3.2 Bioavailability of ceforal-3:
4.3.2.1 Female subjects:
Table 4.3.4 indicates that after oral administration of ceforal-3 in female subjects, mean±SE Cmax of
2.08±0.16 µg/ml was attained at Tmax of 3.87±0.32 hr. Mean±SE values of AUC and AUMC of ceforal-3 in
females were 23.99±1.07 µg.hr/ml and 169.44±7.99 µg.hr2/ml, respectively, with mean±SE MRT of
7.09±0.21 hr.
4.3.2.2 Male subjects:
Table 4.3.5 shows that the mean±SE values of maximum concentration of ceforal-3 in plasma (Cmax),
time to attain Cmax (Tmax), area under the plasma drug concentration versus time curve (AUC), Total Area
under the First Moment Curve (AUMC) and Mean Residence Time (MRT) for ceforal-3 administered in
healthy male subjects were 2.54±0.31 µg/ml, 3.95±0.26 hr, 32.99±5.01 µg.hr/ml,264.13±43.42 µg.hr2/ml
and7.83±0.28 hr. Data has been represented in Table 4.3.5.
4.3.2.3 Gender variation:
Table 4.3.6 represents bioavailability parameters of ceforal-3 in female and male healthy subjects.
The Table indicated that significant (P < 0.05) gender variation for ceforal-3 was found only in values of
AUC (23.99±1.07 µg.hr/ml in females versus 32.99±5.01µg.hr2/ml in males) and AUMC (169.44±7.99
µg.hr/ml in females versus 264.13±43.42 µg.hr2/ml in males). However, the other parameters (Cmax
2.08±0.16 µg/ml versus 2.53±0.31 µg/ml, Tmax 3.87±0.32 hr versus 3.95±0.26 hr and MRT 7.09±0.21 hr
versus 7.83±0.28 hr in females and males, respectively.) showed non significant (P > 0.05) gender
variation.
4.3.3 Bioavailability of cefspan and ceforal-3:
4.3.3.1 Brand variation in female subjects:
As evident from Table 4.3.7, all bioavailability parameters of cefspan and ceforal-3, Cmax, Tmax, AUC,
AUMC and MRT, in female subjects did not show brand variation and were statistically non-significant (P >
0.05).
4.3.3.2 Brand variation in male subjects:
Table 4.3.8 indicates that all respective bioavailability parameters of cefspan and ceforal-3 in male
subjects were non-significantly (P > 0.05) different from each other. Like female subjects, male subjects did
not show brand variation forcefspanandceforal-3.
178
4.3.3.3 Gender variation of cefspan and ceforal-3:
For the purpose of gender variation, results of cefspan and ceforal-3in female and male subjects have
been compared in Table 4.3.9. Mean±SE Tmax and MRT values of cefspan and ceforal-3 in female and male
subjects did not show gender variation and were non-significantly (P > 0.05) different in female and male
subjects. Statistically significantly (P ˂ 0.05) mean±SE Cmax values were found for cefspan in males
(2.93±0.0.24µg/ml) and ceforal-3 in females. However, the highest value of Cmax was found for cefspan in
males followed by in descending order for ceforal-3 in males, cefspan in females and ceforal-3 in females.
Similarly, mean±SE values of AUC for cefspan and ceforal-3 in male and female subjects, respectively, were
found significantly (P < 0.05) different. However, the highest AUC value was found in cefspan for male
(36.58±3.10 µg.hr/ml), those of intermediate for ceforal-3 in males (32.99±5.01 µg.hr/ml) and for cefspan in
females (27.12±2.25 µg.hr/ml) and the lowest one forceforal-3 in females (23.99±1.07 µg.hr/ml). The non-
significantly (P > 0.05) different AUMC values of cefspan and ceforal-3 in males (282.95±23.11 µg.hr2/ml
and 264.13±43.42 µg.hr2/ml) were significantly (P < 0.05) dissimilar to the value of ceforal-3
(169.44±7.99µg.hr2/ml)in females and non-significantly (P > 0.05) different from the value of cefspan
(208.99±18.47 µg.hr2/ml) in females. Nevertheless, the highest value of AUMC was noted for cefspan in
males and lowest one for ceforal-3 in females with intermediate values forceforal-3 in males and cefspan in
females.
4.4 Bioequivalence Studies:
The results regarding bioequivalence of two brands of cefixime i.e. ceforal-3 as test and cefspan as
reference following400 mg oral administration of these two brands in ten healthy adult female and male
subjects with a washout period of seven days have been presented as follows:
4.4.1 Bioequivalence of ceforal-3 and cefspan in female and male subjects:
The parameters of AUC and Cmax of two cefixime brands, cefspan (reference) and ceforal-3(test),
were used to calculate bioequivalence by measuring their relative bioavailability. In healthy adult female
subjects, mean Cmax values observed for test and reference products were2.08µg/ml and 2.24µg/ml,
respectively, with T/R ratio of 0.9286.The AUC values for test and reference formulations were
27.12µg.hr/ml and 23.98µg.hr/ml, respectively, with the ratio of 0.8842 (Table 4.4.1).
In healthy adult male subjects, the Cmax values were 2.54µg/ml and 2.93 µg/ml and the AUC
values were 32.99µg.hr/ml and 36.58µg.hr/ml for test and reference brands, respectively (Table 4.4.2).
The calculated values for ratio of test to reference were 0.9019 for means of Cmax and 0.8669 for means of
AUC.
179
The mean values of Cmax for test and reference brands were non significantly (P > 0.05) different and
similarly respective test and reference values for AUC did not show any significance (P < 0.05) both in
female as well as in male subjects. The relative bioavailability values, based on Cmax (rate of absorption)
and AUC (extent of absorption), in females and males were within the range of 80-125% which are
acceptable for bioequivalence (Table 4.4.1 and Table 4.4.2).
Table 4.4.1: Relative bioavailability for AUC and Cmax of ceforal-3 and cefspan formulations in
females.
Parameter Ceforal-3 (T) Cefspan (R) Ratio (T/R)
Relative
Bioavailability
Statistical
Comparison
Cmax
(µg/ml) 2.08 2.24 0.9286 92.86% NS
AUC
(µg.hr/ml) 23.98 27.12 0.8842 88.42% NS
NS: Non-Significant (P > 0.05)
Table 4.4.2: Relative bioavailability for AUC and Cmax of ceforal-3 and cefspan formulations in
males.
Parameter
Ceforal-3
(T) Cefspan (R) Ratio (T/R)
Relative
Bioavailability
Statistical
Comparison
Cmax
(µg/ml) 32.99 36.58 0.9019 90.19 NS
180
AUC
(µg.hr/ml) 2.54 2.93 0.8669 86.69 NS
NS: Non-Significant (P > 0.05)
181
CHAPTER V
DISCUSSION
Pharmacokinetics and bioequivalence of two brands of cefixime capsule were investigated
following a single oral administration of 400 mg capsule to healthy adult female and male human
subjects. The plasma concentrations of cefixime at various time intervals after oral dose have
been used for describing pharmacokinetic and bioavailability parameters and the results thus
obtained are discussed:
5.1 Plasma concentrations:
During the course of antimicrobial therapy an antibiotic must maintain a certain
therapeutic level or minimum inhibitory concentration (MIC) in plasma. The recommended MIC
for cefixime has been reported in the range of 0.06-1.00 µg/ml (Knapp et al., 1988).
5.1.1 Plasma concentration of cefixime:
In females an upper limit of cefixime MIC was maintained in plasma for 12 hours after
administration of cefspan. The concentration observed after 12 hours of sampling following oral
administration of ceforal-3 in healthy females was less than the upper limit of cefixime MIC
(Table 4.1.4). Maximum plasma concentrations for both brands were observed at 4 hours of
sampling after oral administration in females. After maximum drug level, a progressive decline
in plasma drug concentration was observed. Plasma drug levels did not fall below the lower MIC
limit even after 24 hours of sampling in females (Table 4.1.7). At the last (24 hour) sampling
time of cefixime in females, the plasma concentration observed was 2-3 folds higher than the
lowest MIC limit.
Table 4.1.8 showed that an upper limit of cefixime MIC was maintained in male’s plasma
for more than 12 hours. However plasma levels of the drug did not fall below the lower limit of
MIC even after 24 hours of drug administration in males. So both brands, after a single oral
administration in males, maintained their therapeutic levels till last sampling time. Once
maximum concentration was achieved in plasma, drug level declined progressively, thereafter.
182
Thus cefspan and ceforal-3 both after a single oral administration in female and male healthy
volunteers, maintained their therapeutic levels in plasma till last sampling time of 24 hours. A
progressive decline in the cefixime level was observed in both genders after attaining the
maximum plasma drug concentration. However, lower plasma concentrations with shorter
duration for maintenance of therapeutic concentrations of cefixime in human subjects have been
reported in earlier studies (Brittain et al., 1985; Kees et al., 1990; Westphal et al., 1993; Liu et
al., 2002; Asiri et al., 2005).
5.2 Pharmacokinetics:
The pharmacokinetic parameters determined in the present study were best described by
one compartment open model, using a computer program, MW/PHARM version 3.02 by F.
Rombout, in cooperation with University Centre for Pharmacy, Department of Pharmacology and
Therapeutics, University of Gronigen & Medi/Ware, copy right 1987-1991. Least Square
Regression Analysis was applied to discriminate the best model and Correlation Coefficient was
taken as measure of goodness-of-fit.
Pharmacokinetics behavior of orally administered two brands of cefixime, cefspan and
ceforal-3, has been described in terms of one compartment model in human being.
Pharmacokinetic parameter results of Cefspan and Ceforal-3 capsules following single oral dose
of 400 mg in healthy female and male subjects have been discussed below:
5.2.1 Pharmacokinetics of cefixime:
The biological half life is the time required for 50 percent of the drug to be eliminated
from the body after distribution equilibrium has been attained. It is the time required for a plasma
concentration of a drug to reduce by one-half. Longer half life indicates delayed elimination of
drug and shorter half-life shows rapid elimination from the body (Baggot, 1977). Mean±SE half
life values, 3.99±0.54 and 3.12±0.39 hours, in healthy female subjects and 5.01±0.61 and
4.72±0.72 hours in healthy male subjects were observed after oral administration of cefspan and
ceforal-3, respectively. These half life values were found corresponding to the values, 3.5 hours and
4.2 hours, after 400 mg oral administration of cefixime in healthy young and elderly subjects,
respectively (Baltimore, 2005), 4.9 hours after intravascular 50 mg/kg administration of cefepime
in neonates (Capparelli et al., 2005), 4 hours in adult male volunteers administered with 400 mg
183
cefixime (Kalman and Steven, 1990), 3.09 hours in healthy female and male volunteers after
administration of 200 mg cefixime (Yi et al., 1995) and 3.5 hours and 4 hours following
intravenous administration of cefotetan and ceftizoxime, respectively, in healthy female subjects
(Bergan, 1987 and Deeter et al. 1990). However, shorter half life values have been reported as
1.50 hours and 1.89 hours after 1 g intravenous and intramuscular administration of ceftazidine,
respectively, in female subjects (Sommers et al., 1983), 1.32 hours and 1.35 hours after 1 gram
intravenous administration of cefotaxime and cefoperazone, respectively, in women after 2 -3
postpartum days (Charles and Bryan, 1986), 1.18 hours after 1gmcefotaximeadministration in
healthy adult subjects (Standiford et al., 1982), 2.6 hours following 1g intravenous administration
of cefoperazone in human subjects (Sootornpas et al., 2011) and 3 hours after administration of
400 mg cefixime in males (Low, 1995) and in another study 3 hours after its multiple doses of 50,
100, 200 and 400 mg in healthy male subjects (Brittain et al., 1985).Further, in present study half
life values in healthy adult female and male subjects were shorter than 6.2 hours and 6.77 hours
following administration of 2 g ceftriaxone infusion in healthy volunteers and pregnant patients,
respectively (Bourget et al., 1993), 8.16 hours and 7.60 hours in healthy women after
administration of 250 mg ceftriaxone intravenously and intramuscularly, respectively (Robert et
al., 2001) and 5.4 to 10.9 hours in healthy adult males following 1 g intravenous administration
of ceftriaxone (Kalman and Steven, 1990). The elimination half life of cefixime in local human
subjects have mostly been found longer than those in their foreign counterparts (Table 2.1). It
has been appreciated that half life is a derived parameter which changes as a function of both
clearance and volume of distribution (Gibaldi, 1984). Thus longer half life values in present
study may be attributed to the higher value of Vd and lower values of β and ClB than most
reported values in the literature and converse is also true (Table 2.1).
The apparent volume of distribution (Vd) relates the drug concentration in plasma to the total
amount of the drug in the body after distribution equilibrium has been attained (Gibaldi and Perrier,
1982). It is the theoretical concept that relates the administered dose with the actual initial
concentration present in the circulation (Smith et al., 2001). The more than unity mean±SE values
of volume of distribution recorded in male adults (1.10±0.15 l/kg for cefspan and 1.29±0.21 l/kg for
ceforal-3) and in female adults (1.38±0.22 l/kg for cefspan and 1.36±0.17 l/kg for ceforal-3) of
present investigations reflect excellent tissue penetration of the drug. These values were found to be
higher than the values, 0.26 and 0.5 l/kg, reported in their foreign counterparts following oral
184
administration of 200 mg and 400 mg cefixime, respectively (Faulkner et al., 1987), 0.23 l/kg
following intravenous administration of cefotaxime in healthy adult subjects (Standiford et al.,
1982) and 0.3 l/kg after intravenous administration of 200 mg cefixime (Ziv et al., 1995).Further,
lower values have been reported in women during postpartum period after cesarean section, 0.18
l/kg (Gonik et al., 1986), in female patients of cystic fibrosis, lower respiratory tract infections
and sepsis after administration of cefepime, 0.32 l/kg, 0.22 l/kg and 0.47 l/kg, respectively
(Ambrose et al., 2002), in young and elderly females following intravenous administration of
1gm cefepime, 0.21 l/kg and 0.24 l/kg, respectively (Barbhaiya et al., 1992b). The values of Vd in
present study were found similar to 1.71 l/kg after 200 mg intravenous administration (Duverene et
al., 2012), 1.1 l/kg after 400 mg oral (Guay et al., 1986) and 1.112 l/Kg after 400 mg oral
administration of cefixime in adult male subjects (Guay et al., 1986).However, higher values of
2.2 l/kg and 2.8 l/kg were recorded in dogs following oral doses of 6.25 mg/kg and 25 mg/kg
cefixime, respectively (Bialer et al., 1987) and 8.8 l/kg was recorded in healthy adult males after
parenteral administration of 1 g cephapirin (Kalman and Steven, 1990). Further, higher values
have been reported as 11.7 l/kg and 12.54 l/kg in healthy and pregnant females, respectively,
after infusion of 2gmceftriaxone (Bourget et al., 1993). In the present study, the values of
volume of distribution in healthy subjects were found greater than most values reported in
literature (Table 2.1).The greater value of Vd for cefixime indicates its excellent penetration into
the tissues. Besides intra and inter species biological variations, a possible explanation for the
higher value of Vd in the present study may be linked to the lower extrapolated zero time drug
concentration (B) as compared to that of its higher values in above cited studies.
Total body clearance represents the sum of metabolic and excretory processes and is the
volume of blood completely cleared of a drug in a unit time. It is the sum of all processes which
contributes towards elimination of drug from the body. The mean±SE total body clearance in adult
female subjects (0.27±0.02 l/hr/kg and 0.31±0.02 l/hr/kg for cefspan and ceforal-3, respectively)
and in adult male subjects (0.16±0.02 and 0.21±0.04 l/hr/kg for cefspan and ceforal-3, respectively)
of present study were comparable to 0.28 l/hr/kg in neonates administered with 50 mg/kg
ceftriaxone (Mulhall et al., 1985) and 0.14 l//hr/kg (Guay et al., 1986) and 0.26 l/h/kg (Faulkner et
al., 1988) in healthy adult subjects receiving 400 mg cefixime orally. The values of total body
clearance, 0.24 l/hr/kg and 0.31 l/hr/kg, observed in dogs after intravenous infusion of cefixime at
dose rate of 6.25 mg/kg and 25 mg/kg, respectively (Bialer et al., 1987) have also been found
185
corresponding to the ClB values of cefixime in healthy subjects of present study. The higher
values of ClB have been reported in adults as3.55 l/hr/kg following 200 mg intravenous injection of
cefixime (Duverene et al., 2012), 4.5 l/hr/kg in neonates after administration of 30 mg/kg cefoxitin
(Regazzi et al., 1983), 6.69 l/hr/kg, 9.25 l/hr/kg and 9.87 l/hr/kg in children following dose of 10
mg/kg, 15 mg/kg and 20 mg/kg cefixime, respectively (Alshare, 1999) and 5.38 l/hr/kg for 1000
mg intravenous cefoperazone in women 2-3 days after postpartum (Charles and Bryan, 1986).
However, lower values were observed in healthy humen as 0.02 l/hr/kg, 0.25 l/hr/kg , 0.3 l/hr/kg
and 0.35 l/hr/kg for respective multiple doses of 50 mg, 100 mg, 200 mg and 400 mg cefixime
(Brittain et al., 1985). Further, lower body clearance has been reported as0.03 l/hr/kg for 200 mg
cefixime administered orally in patients suffering from respiratory tract infections (Guay et al.,
1986) and 0.07 l/hr/kg in women following intravenous administration of 2 gm cefoperazone
after surgical delivery (Gonik et al., 1986).
Although in present study the pharmacokinetic parameters of cefixime in local female and
male human being have been found similar, lower and higher than the reported values in literature
yet it may be noted that B, β and ClB remained lower while t1/2 β and Vd remained higher than most
respective values in their foreign counterparts and animals (Table 2.1). A lower total body
clearance (ClB) in local subjects of present study than most reported values in literature may be
attributed to lower values of β as compared to its respective higher reported values (Table 2.1)
while converse is also true (Javed et al., 2003) . It has been reported that cefixime is excreted
unchanged in urine (Faulkner et al., 1988; Barre, 1989; Westphal et al., 1993; Baltimore, 2005).
Lower total body clearance may also be related to reabsorption of major unionized moiety of
acidic cefixime (pKa=2.5) in acidic human urine (pH=5.5-6.5) available at kidney tubular level
(Majid, 2014 and Nisar, 2014). Since the clearance parameter comprises a volume as well as a rate
component (Baggot, 1977), lower total body clearance of cefixime in local subjects may also be
indicative of longer half life and higher volume of distribution of the drug in present study. Thus
the alteration in either ClB or Vd may affect the half life (Prescott and Baggot, 1988). The
differences regarding pharmacokinetic parameters of local subjects of present study may also be
attributed to environmental and genetic variations when compared with those of their foreign
counter parts (Javed et al., 2003; Javed et al., 2009a,b; Hussain et al., 2014).
186
The half life of a drug is a derived parameter that changes as a function of both clearance
and volume of distribution. The apparent volume of distribution of a drug is a function of the
volume of tissues in which drug distributes, partition coefficient of drug between tissues and
circulatory blood, the blood flow to the tissues and binding of drugs to the plasma and tissue
proteins. The total body clearance depends upon blood flow to the organ, fraction of unbound drug
in blood and maximal ability of the organ to remove the drug. Most of these factors are under
environmental and genetic control (Eckland and Danhof, 2000; Javed et al., 2009a,b; Hussain et al.,
2014).
5.3 Bioavailability:
The fraction of the administered dose that reaches the systemic circulation is called
bioavailability. Bioavailability refers both to the rate of the drug absorption and to the extent of
absorption. It is the one of many factors that determines the relation between drug dosage and
intensity of action. Bioavailability is the function of Cmax, Tmax and AUC where Tmax is closely
related to the absorption rate and Cmax depends upon both the extent and rate of drug absorption.
However, drug absorption continues after Cmax has been attained. More is the drug absorption,
higher is the total area under plasma concentration versus time curve (AUC) which represents the
extent of drug absorption. The higher AUC results in the higher bioavailability of the drug. An
increased absorption may lead to increased distribution too. The rate and extent of the absorption
depends upon the pH of the environment, drug solubility, biotransformation, absorption at the
intestinal level, gastric emptying time, gastric motility and systemic circulation toward the
absorption sites. When a drug product shows poor systemic availability, it usually becomes
necessary to distinguish between dosage form and physiologically modified bioavailability
(Krebs, 2001; Parada and Aguilera, 2007).
The differences of Cmax, Tmax and AUC values of current study to that of literature values
have been shown in Table 2.3. Bioavailability parameters of cefixime brands, cefspan and
ceforal-3, were analyzed after single oral administration 400 mg in healthy female and male
subjects and the results were discussed below:
5.3.1 Bioavailability of cefixime:
187
The maximum plasma concentration (Cmax) of cefspan (2.24±0.23 µg/ml and 2.93±0.24
µg/ml) and ceforal-3 (2.08±0.16 µg/ml and 2.53±0.31 µg/ml) following oral dose in healthy adult
female and male subjects, respectively, were smaller than 13.4 and 11.7 µg/ml in healthy female
subjects following oral intake of 500 mg cefaclor with water and juice, respectively (Li et al., 2009)
and 25.2μg/ml, 110μg/ml and 574 µg/ml in neutropenic mice following 25 mg/kg , 100 mg/kg
and 400 mg/kg administration of ceftolozane (Craig and Andes, 2013). The peak plasma
concentrations observed for cefspan and ceforal-3 were found also to be lesser than reported
values in healthy male volunteers as 3.38 μg/ml and 3.45 μg/ml for winex and suprax 200
mg/10ml suspension, respectively (Asiri et al., 2005), 4.74 μg/ml and 4.96 μg/ml for loprax and
reference cefixime 400 mg capsules, respectively (Zakeri et al., 2008), 3.38μg/ml and 3.29 μg/ml
for Tablet and capsule, respectively, of cefixime 200 mg given orally (Lan-Ying et al., 2004) and
6.3 μg/ml and 13.7 μg/ml after oral intake of 1 gram of cefuroxime and cefadroxil, respectively,
in healthy subjects (Kalman and Steven, 1990). The values of Cmax observed in the present study
were found corresponding to 2.17 μg/ml for oral cefixime 400 mg (Jieying et al., 1996), 2.63
μg/ml and 3.85 μg/ml for 200 mg and 400 mg cefixime Tablets, respectively (Brittain et al.,
1985) and 2.317 mg/L and 2.287 mg/L for two brands of 200 mg cefixime capsules, respectively
(Ying et al., 2003) in healthy male subjects. The results were also comparable to 2.95 and 2.43
µg/ml following oral dose of 200 mg cefixime Tablet and syrup, respectively, in healthy female and
male volunteers (Kees et al., 1990) and 2.64 µg/ml following administration of cefixime in patients
of respiratory tract infections (Yi et al., 1995). However, the Cmax values of both brands of cefixime
used in healthy females and males of present study were larger than 0.64 µg/ml and 1.15 µg/ml
(Motohiro et al., 1986) in children administered with 1.5 mg/kg and 3 mg/kg cefixime,
respectively,0.7 µg/ml, 1.2 µg/ml and 2.1 µg/ml following twice a day oral administration of 50
mg, 100 mg and 200 mg cefixime, respectively, in healthy volunteers (Nakashima et al., 1987), 2
µg/ml in healthy adult subjects after oral intake of 300 mg cefdinir (Kalman and Steven, 1990),
0.89 µg/ml in neonates following parental administration of 50 mg/kg cefepime and 1.26 µg/ml
for 50 mg cefixime granules and 1.16 µg/ml for 50 mg capsule of cefixime administered in
human subjects (Motohiro et al., 1986).
The time of the first occurance of Cmax, called Tmax, was found to be 4.05±0.35 hours and
3.87±0.32 hours in healthy female subjects and 4.11±0.16 hours and 3.95±0.26 hours in healthy
male subjects of present study after oral administration of cefspan and ceforal-3 400 mg
188
capsules, respectively. These values were similar to the Tmax, 4 hours, observed after oral
administration of 200 mg cefixime in condition of respiratory tract infection (Yi et al., 1995), 3.3
to 3.5 hours noted after oral administration of 200 mg in healthy state (Kees et al., 1990), 3.7
hours and 3.3 hours for cefixime 200 mg administered in fasting and non-fasting condition,
respectively (Yaoguo et al., 1994), 4 hours for 400 mg Tablet of cefixime in healthy male
volunteers (Healy et al., 1989; Montay et al., 1991) and 4.7 hours (Lan-ying et al., 2004) and 3.7
hours (Duverene et al., 2012) after administration of 200 mg cefixime Tablets in healthy human
volunteers. The time to attain maximum drug concentration (Tmax) in present study were longer
than 0.5 hours and 1.0 hours after administration of 2 g infusion of ceftriaxone in healthy subject
and pregnant patients, respectively (Bourget et al., 1993), 2 hours after administration of Cis and
Trans isomers of cefprozil in lactating females (Shyu et al., 1992), 1.25 hours in females
following 500 mg oral administration of cefaclor (Li et al., 2009), 2 hour after administration of
cefixime 400 mg in healthy males (Low, 1995), 0.25 hours in mice injected with ceftolozane
(Craig and Andes, 2013) and 1.44 hours for cefroxadine (Kang et al., 2006), 1.9 hours for 1 g I/V
cefoperazone (Sootornpas et al., 2011) and 1.5 hours for 1 g I/M ceftriaxone (Meyers et al.,
1983) after administration in healthy adult males. The value of 5.2 hours for cefixime 400 mg
administered orally in healthy men (Liu et al., 2005) and 6.7 hours for cefixime 400 mg
administered in healthy male volunteers (Stone et al., 1988) were found longer than the values
observed in present study.
The area under the plasma concentration-time curve (AUC) is a measure of extent of drug
absorption and reflects the availability of drug in systemic circulation (Shargel and Yu., 1999)
while total area under the first moment of a plasma concentration-time profile (AUMC) is the
total area under the curve resulting from a plot of the time and product of drug concentration and
time. The AUMC is used for assessing the extent of distribution i.e. volume of distribution at
steady state and the persistence of drug in the body (Kwon, 2001). The AUC values in females,
27.12±2.25 µg.hr/ml and 23.99±1.07 µg.hr/ml, and in males, 36.58±3.14 µg.hr/ml and
32.99±5.01 µg.hr/ml were investigated following oral administration of cefspan and ceforal-3,
respectively. The mean±SE values of AUMC for cefspan and ceforal-3 were 208.99±18.47
µg.hr2/ml and 169.44±7.99 µg.hr2/ml, respectively, in females and 282.95±23.11 µg.hr2/ml and
264.13±43.42 µg.hr2/ml in males, respectively. The AUC values of present study were found
similar to 26 µg.hr/ml and 23.6 µg.hr/ml following administration of 200 mg oral solution and
189
200 mg capsule, respectively, in healthy volunteers (Faulkner et al., 1988), 25.8 µg.hr/ml after
administration of 400 mg cefixime in healthy volunteers (Jieying et al., 1996) and 30.22
µg.hr/ml in women intravenously administered with 1 g cefotaxime 2-3 days after postpartum
(Charles and Bryan, 1986). However, AUC values in present study were found smaller than
155.7 µg.hr/ml following administration of 2 g ceftriaxone intravenously (Pletz et al., 2004), 172
µg.hr/ml and 218 µg.hr/ml of cefepime in young and elderly female subjects, respectively
(Barbhaiya et al., 1992b), 179.8 µg.hr/ml and 169.4 µg.hr/ml for ceftazidime 1000 mg
administered intravenously and intramuscularly, respectively, in female subjects (Sommers et al.,
1983), 34.9 µg.hr/ml and 49.5 µg.hr/ml following 400 mg oral dose of cefixime in young and
elderly person, respectively (Baltimore, 2005), 40 µg.hr/ml (Guay et al., 1986) and 38.3 µg.hr/ml
(Healy et al., 1989) after administration of 400 mg Tablet in healthy adult males. Further, the
AUC values of present investigations remained higher than AUC of 15.92 µg.hr/ml and 15.97
µg.hr/ml (Yu-fei et al., 2004), 19.91 µg.hr/ml and 19.09 µg.hr/ml for two brands of cefixime,
respectively, in healthy male volunteers, (Min-ji et al., 2004) 13.3 µg.hr/ml after parenteral
administration of ceftolozane in mice (Craig and Andes, 2013), 6.2 µg.hr/ml in lactating mothers
administered with cefprozil (Shyu et al., 1992) and 2.91, 3.13 and 3.01 µg.hr/ml in group of
healthy female and male subjects administered with cefixime 200 mg Tablet, syrup and dry
suspension, respectively (Kees et al., 1990).
Mean residence time (MRT) is the statistical moment analogy to drug half life. It
provides information related to the time required to eliminate 62.8% of the dose (Gibaldi, 1984).
It is helpful in measuring how longer a drug substance or molecule resides in a compartment.
There are numerous drug molecules that reside in the compartment at a given time; each
molecule enters the compartment through one of the inputs and leaving through one or more of
the outputs. Each molecule may spend a different length of time in the compartment because of
input and output distribution times; moreover there also exists a distribution of time length with
which the drug molecule stays in the compartment. The mean±SE values of MRT for cefspan
and ceforal-3 orally administered in females were 7.69±0.20 hours and 7.09±0.21 hours,
respectively. Mean±SE values of MRT in case of males were 7.79±0.28 hours and 7.83±0.28
hours for cefspan and ceforal-3, respectively. The present MRT values were corresponding to the
literature cited value, 7.47 hr after oral administration of cefixime 400 mg in healthy volunteers
(Jieying et al., 1996). In current study the mean residence time (MRT) for cefixime in indigenous
190
human were shorter than the 9.1 hours for 2 g intravenous ceftriaxone in healthy male and
female subjects (Pletz et al., 2004), 17.81 hours after administration of cephradine 250 mg
capsules in healthy male volunteers (Shoaib et al., 2008), 15 hours after intravenous
administration of 1 g ceftriaxone in cardiac patients (Martin et al., 1996), 29.9 hours after
intravenous administration of ceftriaxone 2 gm in liver transplant recipients (Toth et al., 1991).
The mean residence time (MRT) of cefixime in the present study was longer than the earlier
studied values for cefpodoxime (5.7 hours) and cefixime (6.5 hours) after 400 mg oral
administration (Liu et al., 2005), for 500 mg cephalexin (1.89 hours) in female and male
volunteers (Mircioiu et al., 2007). The values of mean residence time in present study were
found longer than the most literature values in foreign counterparts (Table 2.3). The longer
values of MRT for cefixime were due to respective higher values of AUMC in present study.
In present study bioavailability parameters of Cefixime e.g. Cmax was lower while Tmax,
AUC, AUMC and MRT were higher than most respective reported values (Table 2.3).
5.4 Bioequivalence:
Bioequivalent are chemically equivalent drug products which when given in the same
dosage regimen would result in comparable bioavailability. The bioavailability of drug is
influenced by both pharmaceutical and biological factors (Wagner, 1975). The pharmaceutical
manufacturing unit can control the pharmaceutical factors, while, the biological factors are
uncontrollable. Manufacturing processes have been found to affect the bioavailability and
responses to various drugs (Curry, 1977).
Two or more drug products are bioequivalent if the parameters of rate and amount of
absorption do not show significant (P < 0.05) differences when administered under similar
conditions to human subjects and when their ratios fall between 0.80 to 1.25 (Aboulenein et al.,
2005).
5.4.1 Bioequivalence of cefixime:
191
Bioequivalence studies of generic pharmaceuticals are essential to be compared to the
reference brand products to ensure safety and conformity of these generics. The present study
showed that the test formulation of cefixime (ceforal-3 400 mg) capsule was bioequivalent to the
reference product (cefspan 400 mg) in healthy female and male subjects. Based on T/R ratio values
of AUC and Cmax, relative bioavailability in females (88.46% and 92.86%) and males (90.21% and
86.64%) were found in the range, 80 -125%, for bioequivalence of drugs (Table 4.4.1 and Table
4.4.2). Earlier, bioequivalence of local and imported products of cefixime with T/R ratio of0.1035
have been declared within the acceptance limit of 0.80-1.25 (Yu-fei et al., 2004), while, in another
study the relative bioavailability of cefixime 200 mg Tablet to capsule was 102.8% (Lan-Ying et al.,
2004). Further, Ming-Hui, (2009) observed that 200 mg cefixime Tablet was bioequivalent to 200 mg
cefixime capsule after oral administration in healthy volunteers. Consequently formulations of
cefixime, ceforal-3 as test (local brand) and cefspan as reference (international brand), were
therapeutically bioequivalent and interchangeable in female and male subjects and therefore can be
considered equally effective in medical practice. Moreover, the substitution of the reference product
(cefspan) by the less expensive, yet similarly effective test product (ceforal-3) is justified in both
genders and can be used alternatively in clinical practice.
5.5 Gender variation:
Physiologic differences existing between women and men play a role in prevalence and
outcomes of disease. Gender differences also have implications on pharmacodynamics and
pharmacokinetics of the drugs (Whitley, 2009). Sex-related differences in pharmacokinetics have
been considered as an important determinant for effectiveness (clinical) of drug therapy. The
mechanistic factors resulting in sex-specific pharmacokinetics can be divided into physiological
and molecular factors on basis of which pharmacokinetics in women may be affected when it is
compared with males (Meibohm et al., 2002; Whitley, 2009).
Amongst pharmacokinetic parameters of cefixime higher values of B and t1/2β while
lower values of β, Vd and ClB have been observed in males showing gender variation. Moreover,
bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have higher
values in males also reflecting gender variation. In present study plasma concentrations in male
subjects remained high as compared to those in female subjects (Fig. 4.1.9). The higher plasma
concentrations in males may be linked to more absorption of acidic cefixime from stomach
having more acidic environment than that present in female as stomach of females secretes less
192
gastric acid (Fletcher et al., 1994; Whitley and Lindsey, 2009) than that in males due to low
chloride ion concentration in plasma (Akan et al., 2014). Consequently more unionized moiety
of cefixime having pKa value of 2.5 will be available in stomach of male which is suitable for
absorption rendering higher plasma concentrations. The higher values of Cmax, Tmax, AUC,
AUMC and MRT in males of present study than those of females may be attributed to higher
plasma concentrations as AUC is a measure of extent of drug absorption and reflects the
availability of drug in systemic circulation (Shargel and Yu., 1999) while AUMC is the total area
under the curve resulting from a plot of the time and product of drug concentration and time
reflecting persistence of drug in the body (Kwon, 2001). Further lower values of Vd in males as
compared to that in females may be linked to higher value of B in males and similarly lower
value of ClB in males is due to lower value of Vd and β in males. Further, higher value of t1/2β in
males may be due to lower value of β in males than investigated in females (Table 4.2.9). High
levels of proteins and amino acids have been reported in males as compared to females (Pigoli et
al., 2010) resulting more uric acid excretion in urine making it more acidic (Silaon et al., 1991).
Moreover, higher excretion of chloride in urine of males than in females contributes to more
acidic urine in males (Akan et al., 2014). Cefixime being an acidic drug with pKa=2.5 (Rao et
al., 2010), will be available in more acidic urine of males as unionized moiety of drug which is
suitable for absorption from kidney tubules rendering less urinary excretion in males than that in
females. Urinary excretion of cefixime will build a major portion of total body clearance which
is sum of all metabolic and excretory processes if kidney remains major pathway for excretion of
cefixime (Westphal et al., 1993). So higher clearance of cefspan and ceforal-3in females than
that present in males may be attributed to lower urinary pH in males.
Both the brands, cefspan and ceforal-3, were observed bioequivalent in females as well as
in males. The bioavailability parameters, Cmax and AUC, of both the brands were non-
significantly (P > 0.05) different in both genders. The ratio (T/R) for Cmax was 0.9286 and 0.9019
in females and males, respectively and the relative bioavailability based on AUC was 88.42 and
86.69 in female and male healthy subjects, respectively, which were in the acceptable range of
bioequivalence. So gender difference played no specific role in bioequivalence of different
brands of a drug.
193
Keeping in view the aim and hypothesis of the study differences regarding
pharmacokinetic and bioavailability of two brands of the cefixime were not observed in female
and male subjects. However, some gender variations were found to be present. So, a least
expansive local brand ceforal-3 was found bioequivalent to the most expensive multinational
brand cefspan.
5.6 Conclusions:
1. In indigenous male and female human beings, pharmacokinetic parameters of cefixime
e.g. B, β and ClB have been found to be lower while t1/2β and Vd remained higher than
most respective reported values.
2. Bioavailability parameters of cefixime e.g. Cmax was lower while Tmax, AUC, AUMC and
MRT were higher than most respective values in their foreign counterparts.
3. Higher plasma concentrations of cefixime in males than present in females show gender
variation.
4. Amongst pharmacokinetic parameters higher values of B and t1/2β while lower values of
β, Vd and ClB have been observed in males showing gender variation.
5. Higher values of ClB in females than that in males may be related to more urinary
excretion of acidic cefixime in comparatively less acidic urine in females than reported in
males.
6. Bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have
higher values in males reflecting gender variation.
7. Both formulations of cefixime i.e. ceforal-3 and cefspan are bioequivalent in male and
female genders.
8. Bioequivalence clearly demonstrates that both formulations of cefixime are exchangeable
in clinical practice resulting low cost therapy in patients using locally manufactured
brand, ceforal-3.
194
CHAPTER VI
SUMMARY
The differences of environmental conditions and genetic makeup of man and animals
between drug exporting and importing countries like Pakistan necessitate the investigations of
pharmacokinetic and bioavailability of drugs in local subjects as these differences are manifested
through the variation in pharmacokinetic and bioavailability parameters. Various formulations of
the same drug may show different bioavailability and cannot be used alternatively. This serious
issue may be identified by bioequivalence studies which highlight this difference in the
bioavailability and therapeutic efficacy among formulations of same drug. So, the need of
pharmacokinetic, bioavailability and bioequivalence studies has been increased for local
population. One must consider the genetic, sexual and environmental conditions of individuals
when interpreting plasma drug concentration. Gender, genetic and environmental differences in the
pharmacokinetic, bioavailability and bioequivalence of cefixime were investigated in healthy adult
female and male subjects in this study.
Cefixime is a third generation orally acting cephalosporin, used for the treatment of
different microbial infections. Pharmacokinetics and bioequivalence of cefixime was
investigated in healthy adult female and male human subjects. After through clinical examination
healthy volunteers (n = 20), female volunteers (n = 10) and male volunteers (n = 10), were
selected for the study. Two brands, cefspan and ceforal-3, of cefixime were selected. Each
volunteer was given an oral dose of 400 mg capsule of each brand with a washout period of 7
days. In each experiment a blank blood sample was collected prior to drug administration. More
blood samples were taken with hourly interval up to 6 hours and then on 12 and 24 hours, post
medication. Concentration of cefixime in plasma samples was determined by high performance
liquid chromatographic method. The plasma concentration versus time data was best analyzed by
the one compartment open model for determination of various pharmacokinetic and bioavailability
parameters. Data was statistically analyzed by using student’s paired t-test. Where necessary,
comparison amongst parameters was carried out by applying DMR conditional to the
significance of ANOVA. For bioequivalence, estimates of extent and rate of absorption
195
comparison in terms of AUC and Cmax between the test (ceforal-3) and reference (cefspan)
brands were calculated.
Maximum concentration of cefspan in blood of female and male volunteers was
3.03±0.45 μg/ml and 4.05±0.42 μg/ml, achieved at 3 and 4 hours, respectively, indicating the
good absorption of cefspan in males. Comparatively maximum plasma concentration of ceforal-3
in females and males were observed as 3.07±0.30 μg/ml and 3.47±0.56 μg/ml, respectively, at 4
hours each. So the highest plasma cefixime concentration was observed in males administered with
cefspan and the lowest in females given ceforal-3.The plasma concentration was lower in females
throughout the sampling duration. The plasma concentration versus time data was applied on an
APO PC-Computer Program MW/PHARM version 3.02by using one compartment open model for
calculation of various parameters.
The extrapolated zero time plasma concentration of cefspan was 5.14±0.74 μg/ml and
5.94±0.78 μg/ml and of ceforal-3 was 5.31±0.57 μg/ml and 5.45±0.86 μg/ml in healthy female
and male subjects, respectively. Elimination rate constant values were 0.21±0.03 hr-1and
0.25±0.03 hr-1in females and 0.16±0.02 hr-1and 0.18±0.03 hr-1in males after oral administration
of cefspan and ceforal-3, respectively. The half life values were found 3.99±0.54 hr and
3.12±0.39 hr in local adult female subjects and 5.01±0.61 hr and 4.72±0.72 hr in healthy adult
male subjects following administration of cefspan and ceforal-3, respectively. The values of
volume of distribution in local adult female and male volunteers were 1.38±0.22 l/kg and
1.10±0.15 l/kg, respectively, for cefspan and 1.36±0.17 l/kg and 1.29±0.21 l/kg, respectively, for
ceforal-3.The total body clearance for cefspan and ceforal-3 were 0.27±0.02 l/hr/kg and
0.31±0.02 l/hr/kg, respectively, in local females and 0.16±0.02 l/hr/kg and 0.21±0.04 l/hr/kg,
respectively, in local males.
Cefspan had Cmax value of 2.24±0.23 μg/ml and 2.93±0.24 μg/ml, Tmax value of
4.05±0.35 hr and 4.11±0.16 hr, AUC value of 27.12±2.25 μg.hr/ml and 36.58±3.10 μg.hr/ml,
AUMC value of 208.99±18.47 μg.hr2/ml and 282.95±23.11 μg.hr2/ml and MRT values of
7.69±0.20 hr and 7.79±0.28 hr, in healthy female and male volunteers, respectively.The values of
AUC 23.99±1.07 μg.hr/ml and 32.99±5.01 μg.hr/ml, Cmax 2.08±0.16 μg/ml and 2.53±0.31μg/ml,
Tmax 3.87±0.32 hr and 3.95±0.26 hr, AUMC 169.44±7.99 μg.hr2/ml and 264.13±43.42 μg.hr2/ml
196
and MRT 7.09±0.21 hr and 7.83±0.28 hr were noted for ceforal-3 administered in female and
male subjects, respectively.
In indigenous male and female human beings, pharmacokinetic parameters of cefixime
e.g. B, β and ClB have been found to be lower while t1/2β and Vd remained higher than most
respective reported values. Bioavailability parameters of cefixime e.g. Cmax was lower while
Tmax, AUC, AUMC and MRT were higher than most respective values in their foreign
counterparts. Higher plasma concentrations of cefixime in males than present in females show
gender variation. Amongst pharmacokinetic parameters higher values of B and t1/2β while lower
values of β, Vd and ClB have been observed in males showing gender variation.
Higher values of ClB in females than that in males may be related to more urinary
excretion of acidic cefixime in comparatively less acidic urine in females than reported in males.
Bioavailability parameters e.g. Cmax, Tmax, AUC, AUMC and MRT were found to have higher
values in males reflecting gender variation. Both formulations of cefixime i.e. ceforal-3 and
cefspan are bioequivalent in male and female genders. Bioequivalence clearly demonstrates that
both formulations of cefixime are exchangeable in clinical practice resulting low cost therapy in
patients using locally manufactured brand, ceforal-3.
197
REFERENCES
Abdulbaqi D and SM Rab, 1996. Changing Spectrum of Thypoid. J Pak Med Assoc, 46(3): 50-
52.
Abdullah A and JD Baggot, 1984. Influence of Escherichia Coli Endotoxin-Induced Fever on
Pharmacokinetics of Imidocarb in Dogs and Goats. Am J Vet Res, 45: 2645-2648.
Aboul‐Enein HY, LI Abou‐Basha, LF Wahman, HA Gharib and WH Tantway, 2005.
Pharmacokinetic Parameters and Relative Bioavailability of Two Tablet Formulations of
Enalapril Maleate. Instrum Sci Technol, 33(1): 1-8.
Acharya G, C Chrles, T Butler, H O May, M Tiwari, K Stoeckel a n d C A Bradley, 1994.
Pharmacokinetics of Ceftriaxone in Patients with Typhoid Fever. Antimicrob Agents Ch,
38: 2415-2418.
Adam D, U Hostalek and K Troster, 1995. 5-Day Cefixime Therapy for Pharyngitis and/or
Tonsillitis: Comparison With 10-Day Penicillin-V Therapy. Infection, 23(2): 83-86.
Adam E, AEM Saeed and IE Barakat, 2012. Development and Validation of a High Performance
Liquid Chromatography Method for Determination of Cefixime Trihydrate and its
Degraded Products Formed Under Stressed Condition of UV Light. Int J Pharm and Sci
Res, 3(2): 469-473
Affrime M and MM Reidenberg, 1975. The Protein Binding of Some Drugs in Plasma from
Patients with Alcoholic Liver Disease. Europ J Clin Pharmacol, 8: 267-269.
Afkhami A, F Soltani-Felehgari and T Madrakian, 2013. Gold Nanoparticles Modified Carbon
Paste Electrode as an Efficient Electrochemical Sensor for Rapid and Sensitive
Determination of Cefixime in Urine and Pharmaceutical Sample. Electrochim Acta, 103:
125-133.
Aguiar AJ, LM Wheeler, S Fusari and JE Zelmer, 1968. Evaluation of Physical and
Pharmaceutical Factors Involved in Drug Release and availability from chloramphenicol
Capsules. J Pharmacol Sci, 57(11): 1844-1850.
198
Ahmad I, 1984. Bioavailability, Pharmacokinetics and Urinary Excretion of Ampicillin in Sheep.
M. Sc. Thesis, University of Agriculture, Faisalabad. Pakistan.
Ahmad M, 1983. Disposition Kinetics of Chloramphenicol in Dogs and Renal Clearance of
Choramphenicol in Goats. M. Sc. Thesis, Department of Physiology and Pharmacology,
University of Agriculture, Faisalabad, Pakistan.
Ahmed SM, AA Elbashir, FE Suliman and HY Aboul-Enein, 2013. New Spectrofluorimetric
Method for Determination of Cephalosporins in Pharmaceutical Formulations.
Luminescence, 28(5): 734-741.
Akan JC, OA Sodipo, Y Liman and ZM Chellube, 2014. Determination of Heavy Metals in
Blood, Urine and Water Samples by Inductively Coupled Plasma Atomic Emission
Spectrophotometer and Fluoride Using Ion-Selective Electrode. J Anal Bioanal Tech,
5(6): 1-7.
Albarellos GA, L Montoya, PC Quaine and MF Landoni, 2011. Pharmacokinetics and
Bioavailability of a Long-Acting Formulation of Cephalexin after Intramuscular
Administration to Cats. Res Vet Sci, 91(1): 129-131.
Aleti SR, D Rangaraju, A Kant, MM Shankraiah, JSI Venkatesh, RN Rao and C Nagesh, 2001.
Solubility and Dissolution Enhancement of Cefixime Using Natural Polymer by Solid
Dispersion Technique. IJRPC, 1(2): 283-288.
Ali I, ZA AL-Othman, HY Aboul-Enein, K Saleem and I Hussain, 2011. Fast Analysis of Third-
Generation Cephalosporins in Human Plasma by SPE and HPLC Methods. LCGC.
Ali T and AM Omair, 2012. In Vitro Interaction Study of Cefixime with Diclofenac Sodium,
Flurbiprofen, Mefenamic Acid and Tiaprofenic Acid. J Chem Pharm Res, 4(6): 2911-
2918.
Ali T and OA Mohiuddin, 2012. In Vitro Interaction Study of Cefixime with Diclofenac Sodium,
Flurbiprofen, Mefenamic Acid and Tiaprofenic Acid. J Chem Pharm Res, 4: 2911-2918.
Alleyne GAO, 1967. The Effect of Severe Calorie Malnutrition on the Renal Function of
Jamaican Children. Paediatr, 39: 400-411.
Alshare M, 1999. Pharmacokinetics of Third Generation Cephalosporins in Children with
Typhoid Fever. Ph. D. Thesis, HEJ Research Institute of Chemistry, International Center
for Chemical Science/Faculty of Pharmacy, University of Karachi, Karachi, Pakistan.
199
Ambrose PG, RC Owens, MJ Garvey and RN Jones, 2002. Pharmacodynamic Considerations in
the Treatment of Moderate to Severe Pseudomonal Infections with Cefepime. J
Antimicrob Ch, 49: 445-453.
Ameyama S, S Onodera, M Takahata, S Minami, N Maki, K Endo, H Goto, H Suzuki and Y
Oishi, 2002. Mosaic-Like Structure of Penicillin-Binding Protein 2 Gene (Pen A) In
Clinical Isolates of Neisseria Gonorrhoeae with Reduced Susceptibility to Cefixime.
Antimicrob Agents Ch, 46: 3744-3749.
Archer GL and Polk RE, 1998. Treatment and Prophylaxis of Bacterial Infections. In: Harrison's
Principles of Internal Medicine 14th Ed, (Isselbacher, K.J., Braunwald, E., Wilson, J.D.,
Martin, J.B., Fauci, A.S. and Kasper, D.L., eds): McGraw-Hill, Inc (Health Professions
Division), pp: 859.
Arshad HM, S Gauhar, R Bano and IN Muhammad, 2009. Development of HPLC-UV Method
for Analysis of Cefixime in Raw Materials and in Capsule. J Pharmacol Sci, 2(1): 53-65.
Asiri YA, MS Al-Said, KI Al-Khamis, EM Niazy, YM El-Sayed, KA Al-Rashood, MJ Al-
Yamani, IA Alsarra and SA Al-Balla, 2005. Comparative Bioavailability Study of
Cefixime (Equivalent to 100 mg/5 ml) Suspension (Winex Vs Suprax) In Healthy Male
Volunteers. Int J Clin Pharm Th, 43(10): 499-504.
Assael BM, 1982. Pharmacokinetics and Drug Distribution during Postnatal Development.
Pharmacol Therapeut, 18: 159-197.
Ayman M, DVM Goudah and MH Sherifa, 2013. Pharmacokinetics and Distribution of
Ceftazidime to Milk after Intravenous and Intramuscular Administration to Lactating
Female Dromedary Camels (Camelus Dromedaries). JAVMA J Am Vet Med A, 243(3):
424-429.
Azmi SNH, B Iqbal, NSH Al-humaimi, IRS Al-salmani, NAS Al-ghafri and N Rehman,
2013.Quantitative Analysis Of Cefixime Via Complexation With Palladium(Ii) In
Pharmaceutical Formulations By Spectrophotometry. J Pharm Anal, 3(4): 248-256.
Baggot JD, 1977. Principles of Drug Disposition in Domestic Animals. In: The Basis of
Veterinary Pharmacology. W.B. Saunders Co. Philadelphia, pp: 144-218.
Bajaj H, S Bisht, M Yadav and V Singh, 2011. Bioavailability Enhancement: A Review. Int J
Pharma Bio Sci, 2: 202-216.
Ballard DE, 1974. Pharmacokinetics and Temperature. J Pharmacol Sci, 36: 1345-1358.
200
Baltimore MD, 2005. Lupin, Suprax (cefixime) for Oral Suspension, USP 100 mg/5 mL
prescribing information; 2005 Aug.
Baraona E, CS Abittan, K Dohmen, M Moretti, G Pozzato, ZW Chayes, C Schaefer and CS
Lieber, 2001. Gender Differences in Pharmacokinetics of Alcohol. Alcohol Clin Exp Res,
25(4): 502–507.
Barbhaiya RH, CA Knupp and KA Pittman, 1992b. Effect of Age and Gender on
Pharmacokinetic of Cefepime. Antimicrob Agents Ch, 36(6): 1181-1185.
Barbhaiya RH, Lotte W., Wen CS and Kenneth AP, 1992a. Absolute Bioavailability of Cefprozil
after Oral Administration in Beagles. Antimicrob Agents Ch, 36 (3): 687-689.
Barbhaiya RH, ST Forgue, VR Gleason, CA Knupp, KA Pittman, DJ Weidler and RR Martin,
1990c. Safety, Tolerance, and Pharmacokinetic Evaluation of Cefepime after
Administration of Single Intravenous Doses. Antimicrob Agents Ch, 34 (6): 1118-1122.
Barbhaiya RH, UA Shukla, CR Gleason, WC Shyu and KA Pittman, 1990. Comparison of the
Effects of Food on the Pharmacokinetics of Cefprozil and Cefaclor. Antimicrob Agents
Ch, 34(6): 1210-1213.
Barbhaiya RH, UA Shukla, CR Gleason, WC Shyu, RB Wilber and KA Pittman, 1990a.
Comparison of Cefprozil and Cefaclor Pharmacokinetics and Tissue Penetration.
Antimicrob Agents Ch, 34(6): 1204-1209.
Barbhaiya RH, UA Shukla, CR Gleason, WC Shyu, RB Wilber, RR Martin and KA Pittman,
1990b. Phase 1 Study of Multiple-Dose Cefprozil and Comparison with Cefaclor.
Antimicrob Agents Ch, 34 (6): 1198-1203.
Barnes JN and FJ Goodwin, 1983. Dihydrocodeine Narcosis in Renal Insufficiency. BMJ-Brit
Med J, 286: 438-439.
Barr WH, LM Gerbract, K Utchen, M Plant and N Strahl, 1972. Assessment of the Biologic
Availability of Tetracycline Products in Man. Clin Pharmacol Ther, 13: 97-108.
Barre J, 1989. Pharmokinetic Properties of Cefixime. Presse Med, 18: 1578-1582.
Barro G, DB Sharma and RK Rama, 1985. Pharmacokinetics of Phenytoin in Protein Energy
Malnutrition. Indian J Pharmacol, 17: 77-78.
Barza M, 1978. The Nephrotoxicity of Cephalosporin: An Overview. J Infect Dis, 137: 560-573.
Basu A, K Basak, M Chakraborty and IS Rawat, 2011. Development and Validation of High
Performance Liquid Chromatographic Method for Simultaneous Estimation of Potassium
201
Clavulanate and Cefixime Trihydrate in Tablet Dosage Form. J Pharm Res, 4(5): 1319-
1321.
Begue P, N Garabcdian, B Quinet and S Baron, 1 9 89 . Tonsillar Diffusion of Cefixime in
Children. Presse Med, 18: 1593-1595.
Beierle I, B Meibohm and H Derendorf, 1999. Gender Differences in Pharmacokinetics and
Pharmacodynamics. Int J Clin Pharm Th, 37(11): 529-547.
Bennett S, R Wise, D Weston and J Dent, 1983. Pharmacokinetics and Tissue Penetration of
Ticarcillin Combined With Calvulanic Acid. Antimicrob Agents Ch, 23: 83l-834.
Beovic B, A Mrhar, R Karba, T Zupancic, I Grabnar, A Belic and M G Marica, 1999a. Influence of
Fever on Cepazolin Pharmacokinetics. J Chemotherapy, 11: 40-45.
Beovic B, A Mrhar, R Karba, T Zupancic, I Grabnar, A Belts and M G Marica, 1999b. Influence of
Fever on the Pharmacokinetics of Ciprofloxacin. Int J Antimicrob Ag, 11: 81-85.
Beresford CH, RJ Neale and OG Brooks, 1971. Iron Absorption and Pyrexia. Lancet, 1: 568-572.
Berg MJ, 1999. Drugs, Vitamins, and Gender. JGSM, 2: 18-20.
Bergan T, 1987. Pharmacokinetic Properties of the Cephalosporins. Drugs. 34(2): 89-104.
Bhagawati ST, SN Hiremath and SA Sreenivas, 2005. Comparative evaluation of disintegrants
by formulating cefixime dispersible tablets. Indian J Pharm Educ, 39(4): 194-197.
Bhutta ZA, LA Kahn and M A Molla, 1994. Therapy of Multi Drug-Resistant Typhoid Fever with
Oral Cefixime vs. Intravenous Ceftriaxone. Pediatr Infect Dis J, 13: 990-994.
Bialer M, A P Tonelli, D Kantrowitz and A Yacobi, 1 9 8 6 . Serum Protein Binding of New Oral
Cephalosporin, CL284; 635, in Various Species. Drug Metab Dispos, 14: 132-36.
Bialer M, WH Wu, ZM Look, BM Silber and A Yacobi, 1987. Pharmacokinetics of Cefixime after
Oral and Intravenous Doses in Dogs: Bioavailability Assessment for a Drug Showing
Nonlinear Serum Protein Binding. Res Commun Chem Pathol Pharmacol. 56(1): 21-32.
Bissell DM and LE Hammaker, 1976. Cytochrom P-450 Heme and the Regulation of Hepatic
Heme Oxygenase Activity. Arch Biochem Biophys, 176: 91-102.
Blaschke TF, PJ Meffin and K L Melmon, 1 9 7 5 . Influence of Acute Viral Hepatitis on Phenytoin
Kinetics and Protein Binding. Clin Pharmacol Ther, 17: 685-691.
Blickenstaff D and M I Grossman, 1 9 5 0 . A Quantitative Study of Gastric Acid Secretion Associated
with Pyrexia. Am J Physiol, 160: 567-571.
202
BNF (British National Formulary), 2011. BMJ Group and the Royal Pharmaceutical Society of
Great Britain, London, United Kingdom.
Bolme P, M Eriksson, L Paalzow, G Stintzing, G Zerihun and Woldemariam, 1995.
Malnutrition and Pharmacokinetics of Penicillin in Ethiopian Children. Pharmacol and
Toxicol, 76 (4): 259-262.
Boreus LO, 1982. Principles of Pediatric Clinical Pharmacology.
In: Boreus L.O., ed. Monographs in Clinical Pharmacology, NY: Churchill Livingstone,
New York, pp.76.
Borin MT, 1991. A review of the pharmacokinetics of cefpodoxime proxetil. Drugs. 42(3): 13-
21.
Bosso JA, GM Chan and JM Matsen, 1983. Cefoperazone Pharmacokinetics in Preterm
Infants. Antimicrob Agents Chemother, 23(3): 413–415.
Bourget P, H Fernandez, V Quinquis and C Delouis, 1993. Pharmacokinetics and Protein
Binding of Ceftriaxone during Pregnancy. Antimicrob Agents Ch, 37(1): 54-59.
Bowie WR, CE Shaw, DGW Chan and WA Black, 1987. In Vitro Activity of Ro 15-8074, Ro
19-5247, A-56268, and Roxithromycin (RU 28965) against Neisseria Gonorrhoeae and
Chlamydia Trachomatis. Antimicrob. Agents Chemother, 31: 470-472.
Brahmaiah B, K Sreenivasulu, M Rajwardanreddy, MS Sowjanya, S Nama and C Baburao,
2013. Enhancement of dissolution rate of cefiximetrihydrate by using various solid
dispersion techniques. Int J Pharm Ther, 4(3): 140-147.
Branch RA and DG Shand, 1976. Propranolol Disposition in Chronic Liver Disease: A Physiological
Approach. Clin Pharmacokinet, 1: 264-279.
Branch RA, J James and AE Read, 1 9 7 6 . A Study of Factors Influencing Drug Disposition in
Chronic Liver Disease Using the Model Drug (+) Propranolol. Brit J Clin Pharmaco, 3: 243-
249.
British Pharmacopoeia, 2011. Stationery Office, London, United Kingdom.
Brittain DC, BE Scully, T Hirose and H C Neu, 1 9 8 5 . The Pharmacokinetics and
Baclericidal Characteristics Activity of Oral Cefixime. Clin Pharmacol Ther, 38:
590-594.
Broderson R, B Friis-Hansen and L Stem, 1983. Drug-Induced Displacement of Bilirubin from
Albumin in the Newborn. Dev Pharmacol Ther, 6: 217-229.
203
Brogden RN, DM Campoli-Richards, 1989. Cefixime: A Review of its Antibacterial Activity.
Pharmacokinetic Properties and Therapeutic Potential. Drugs. 38(4): 524-550.
Bryan JP, H Rocha and WM Scheld, 1986. Problems in Salmonellosis: Rational for Clinical
Trials with Newer Beta-Lactam Agents and Quinolones. Rev Infect Dis, 8: 189-207.
Buchanan N, M D Davis, DB Hendmson, JC Mucklow a nd MD Rawlins, 1 9 8 0 b .
Acetanilide Pharmacokinetics in Kwashiorkor. Brit J Clin Pharmaco, 9: 525-526.
Buchanan N, M D Davis, M Danhof a n d D D Breimer, 1980a. Antipyrine Metabolite
Formation in Children in the Acute Phase of Malnutrition and After Recovery. Brit J Clin
Pharmaco, 10: 363-368.
Butler T, NN Linh, K Arold and M Pollock, 1993. Chloramphenicol-Resistant Typhoid Fever in
Vietnam Associated with R-factor. Lancet, 2: 983-985.
Butt S, 1996. Bioavailability of Spiramycin in Male Volunteers. M. Sc. Thesis, Department of
Biochemistry, University of Agriculture, Faisalabad, Pakistan.
Cao XT, R Kneen, TA Nguyen, DL Truong and CM Parry, 1999. A Comparative Study of
Ofloxacin and Cefixime Pretreatment of Typhoid Fever in Children. Pediatr Infect Dis J,
18: 245-248.
Capparelli E, C Hochwald, M Rasmussen, A Parham, J Bradley and F Moya, 2005. Population
Pharmacokinetics of Cefepime in the Neonates, antimicrob Agents Chemother, 49(7):
2760-2766.
Carcas AJ, P Guerra and J Frias, 2001. Gender Differences in the Disposition of Metronidazole.
Int J Clin Pharm Th, 39(5): 213-218.
Carli S, C Montesissa, O Sonzogni and M Madonna, 1986. Pharmacokinetics of Sodium
Cefoperazone in Calves. Pharmacol Res Commun, 18: 481-490.
Carrasco MDC and JF Francisco, 2011. Gender Differences in the Pharmacokinetics of Oral
Drugs. Pharmacology and Pharmacy, 2011, 2, 31-41.
Carrasco MDC, L Miguel and JF Francisco, 2008. Evaluation of Gender in the Oral
Pharmacokinetics of Clindamycin in Humans. Biopharma Drug Dispos, 29(7): 427-430.
Carroll K and L Reimer, 1996. Review Microbiology and Laboratory Diagnosis of Upper
Respiratory Tract Infections. Clin Infect Dis, 23(3): 442-448.
204
Cerrutti JA, NB Quaglia and A Brandoni, 2002. Effects of Gender on the Pharmacokinetics of
Drugs Secreted by the Renal Organic Anions Transport System in the Rat. Pharmacol
Res, 45: 107-112.
Chambers HF, WK Hadley and E Jawetz, 1998. Beta-Lactam and Other Inhibitors of Cell Wall
Synthesis, In: Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, p.
725.
Chandra J, RK Marwaha and S Sachdeva, 1 9 8 4 . Chloramphenicol Resistant Salmonella Typhi:
Therapeutic Considerations. Indian J Pediatr, 51: 567-570.
Chang HC, 1993. Gasric Secretion in Fever and Infectious Disease. J Clin Invest, 12: 155-169.
Charles D and L Bryan, 1986. Pharmacokinetics of Cefotaxime, Moxalactam and Cefoperazone
in the Early Puerperium. Antimicrob Agents Ch, 29(5): 873-876.
Cheek DB, D Mellite and D Elliott, 1 9 6 6 . Body Water, Height and Weight during Growth in
Normal Children. Am J Dis Child, 112(4): 312-317.
Chiou WL, 1972. Determination of Physiologic Availability of Commercial Phenylbutazone
Preparations. J Clin Pharmacol New Drugs, 12(7): 296-300.
Choi DH and PB Jin, 2007. Bioequivalence Evaluation of Two Brands of Cefixime 100 mg
Capsule (Suprax and Alpha-Cefixime) in Korean Healthy Volunteers. J Appl Pharmacol,
15(3): 182-186.
Chugh K and S Agrawal, 2003. Cefpodoxime: Pharmacokinetics and Therapeutic Uses. Indian J
Pediatr, 70(3): 227-31.
Comford PM, WM Pardridge and LD Braun, 1983. Increased Blood-Brain Barrier Transport of Protein-
Bound Anticonvulsant Drug in the Newborn. J Cereb Blood Flow Metab, 3: 280-286.
Conil JM, B Georges, M Lavit, J Laguerre, K Samii, G Houin and S Saivin, 2007. A Population
Pharmacokinetic Approach to Ceftazidime Use in Burn Patients: Influence of Glomerular
Filtration, Gender and Mechanical Ventilation. Br J Clin Pharmacol, 64(1): 27–35.
Cortell S and M E Conral, 1 9 7 6 . Effect of Endotoxin on Iron Absorption. Am J Phys, 213: 43-47.
Cortes J, G Gamba, A Contertas and J C Pena, 1 9 9 0 . Amikacin Nephrotoxicity in Patients with
Chronic Liver Disease. Rev Invest Clin, 42: 93-8.
Counts GW, LK Baugher, BK Ulness and DJ Hamilton, 1988. Comparative in Vitro Activity of
the New Oral Cephalospo-Rin Cefixime. Eur J Clin Microbiol Infect Dis, 7: 428-431.
205
Craig WA and DR Andes, 2013. In Vivo Activities of Ceftolozane, a New Cephalosporin, with
and without Tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae,
Including Strains with Extended-Spectrum Beta-Lactamases, in the Thighs of
Neutropenic Mice. Antimicrob Agents Ch, 57(4): 1577–1582.
Curry SH, 1977. Drug Disposition and Pharmacokinetics 2nd ed, Black-well scientific
publication, oxford, UK, pp 133-44.
David W, Megran, L Katherine, W Val and R William, 1990. Single-Dose Oral Cefixime versus
Amoxicillin plus Probenecid for the Treatment of Uncomplicated Gonorrhea in Men.
Antimicrob Agents Chemother, 34(2): 355-357.
Deeter RG, MP Weinstein, KA Swanson, JS Gross and LC Bailey, 1990. Crossover Assessment
of Serum Bactericidal Activity and Pharmacokinetics of Five Broad-Spectrum
Cephalosporins in the Elderly. Antimicrob Agents Ch, 34(6): 1007-1013.
Deguchi Y, R Koshida, E Nakashima, R Watanabe, N Taniguchi and F Ichimura, 1988.
Interindividual Changes in Volume of Distribution of Cefazolin in Ewborn Infants and its
Prediction Based on Physiological Pharmacokinetic Concepts. J Pharm Sci, 77: 674-8.
Demotes-Mainard P, H Albin, JM Ragnaud, H Gin, G Vincon and J Aubertin, 1 9 8 8 . Influence of
Hyperthermia on the Pharmacokinetics o f cefotaxime. Pathol Biol, 36: 155-158.
Deshpandea MM, VS Kastureb and SA Gosavi, 2010. Application of HPLC and HPTLC for the
Simultaneous Determination of Cefixime Trihydrate and Ambroxol Hydrochloride in
Pharmaceutical Dosage Form. Eurasian J Anal Chem, 5(3): 227-238.
Devika GS, M Sudhakar and JV Rao, 2010. Validated TLC Densitometric Method for the
Quantification of Cefixime Trihydrate and Ornidazole in Bulk Drug and in Tablet Dosage
Form. Der Pharma Chemica, 2(6): 97-104.
Dhib M, B Moulin, A Leroy, B Hameau, M Godin, R Johannides and JP Fillastre, 1991.
Relationship between Renal Function and Disposition of Oral Cefixime. Eur J Clin
Pharmacol, 41(6): 579–583.
Dhib M, B Moulin, A Leroy, B Hameau, M Godin, R Johannides and JP Fillastre, 1991. Relationship
between Renal Function and Disposition of Oral Cefixime. Europ J Clin Pharmacol, 41: 579-583.
Dhoka MV, SJ Sandage and SC Dumbre, 2010. Simultaneous Determination of Cefixime
Trihydrate and Dicloxacillin Sodium in Pharmaceutical Dosage Form by Reversed-Phase
High-Performance Liquid Chromatography. J AOAC Int, 93(2): 531-535.
206
Dhoka MV, VT Gawande and PP Joshi, 2013. Validated Hptlc Method for Determination of
Cefixime Trihydrate and Erdosteine in Bulk and Combined Pharmaceutical Dosage
Form. Eurasian J Anal Chem, 8(3): 99-106.
Donovan MD, 2005. Sex and Racial Differences in Pharmacological Response: Effect of Route
of Administration and Drug Delivery System on Pharmacokinetics. J Womens Health,
14(1): 30-37.
Donowitz GR and GL Mandell, 1 9 8 8 . Beta-lactam Antibiotics. New Engl J Med, 318: 4l9-426.
Dost FH, 1949. Die Clearance. Klin Wochschr. 21: 257-264.
Dreshaj SH, T Doda-Ejupi, IQ Tolaj, A Mustafa, S Kabashi, N Shala, NJ Geca, A Aliu, A Daka
and N Basha, 2011. Clinical Role of Cefixime in Community-Acquired Infections.
Prilozi, 32(2): 143-155.
Drusano GL, HC Standiford, B Fitzpatrick, J Leslie, P Tangtatsawasdi, P Ryan, B Tatem, MR
Moody and CC Schimpff, 1984. Comparison of the Pharmacokinetics of Ceftazidime and
Moxalactam and their Microbiological Correlates in Volunteers. Antimicrob Agents
Chemother, 26(3): 388-93.
Dube A, S Pillai, S Sahu and N Keskar, 2011. Spectrophotometric Estimation of Cefixime and
Ofloxacin from Tablet Dosage Form. Int J Pharm Life Sci, 2(3): 629-632.
Duverne C, A Bouten, A Deslandes, JF Westphal, JH Trouvin, R Farinotti and C Carbon, 2012.
Modification of Cefixime Bioavailability by Nifedipine in Humans: Involvement of the
Dipeptide Carrier System. Antimicrob Agents Ch, 36(11): 2462-2467.
Eckland DA and M Danhof, 2000. Clinical Pharmacokinetics of Pioglitazone. Exp Clin
Endocrinol Diabetes, 108: S234-S242.
Edelman R and MM Levin, 1 9 8 6 . Summary of an I nternational Workshop on Typhoid Fever. Rev
Infect Dis, 8: 329-349.
Elbashir A, SMA Ahmed and HY Aboul-Enein, 2011. New Spectrofluorimetric Method for
Determination of Cephalosporins in Pharmaceutical Formulations. J Fluoresc, 22(3): 857-
864.
Eldalo AS, AS Ali, HI Shaddad and AH Mohamed, 2004. Pharmacokinetic Study of Cefixime in
Sheep and Cattle. J Anim Vet Adv, 3(1): 36-38.
207
Elkomy MH, P Sultan, DR Drover, E Epshtein, JL Galinkin and B Carvelho, 2014.
Pharmacokinetics of Prophylactic Cefazolin in Parturients Undergoing Cesarean
Delivery. Antimicrob Agents Ch, 58(6): 3504–3513.
Eriksson M, L Paalzow, P Bolme and TW Mariam, 1983. Chloramphenicol Pharmacokinetics
in Ethiopian Children of Differing Nutritional Status. Europ J Clin Pharmacol, 24: 89-92.
Esimone CO, FB Okoye, BU Onah, CS Nworu and EO Omeje, 2008. In Vitro Bioequivalence
Study of Nine Brands of artesunate Tablets Matketed in Nigeria. J Vector Borne Dis, 45:
60-65.
Evene E, M Brault, M Manche, M Sibille, G Montay and DD Vital, 2001. Bioequivalence Study
of Two Formulations (Sachet and Tablet) of Cefixime after Single Oral Doses of 200mg
in Healthy Male Volunteers. Clin Drug Invest, 21(4): 287-294.
Falkowaski AJ, ZM Look, H Noguchi and BM Silber, 1987 . Determination of Cefixime in
Biological Sample by Reversed Phase High Performance Liquid Chromatography. J
Chromatogr, 422: 1 45-152.
Faulkner RD, A Yacobi, JS Barone and A Kaplans, 1 9 8 7 b . Pharmacokinetic Profile of
Cefixime in Man. Pediatr Infect Dis J, 6: 963-970.
Faulkner RD, LL Sia, JS Barone, SJ Forbes and BM Silber, 1989. Bioequivalency of Oral
Suspension Formulations of Cefixime. Biopharm Drug Dispos, 10(2): 205-211.
Faulkner RD, P Fernandez, G Lawrence, LL Sia, AJ Falkowski, AI Weiss, A Yacobi and BM
Silber, 1988. Absolute Bioavailability of Cefixime in Man. J Clin Pharmacol. 28(8): 700-
706.
Faulkner RD, W Bohaychuk, JD Haynes, RE Desjardine and A Yacobi, 1987a. The
Pharmacokinetics of Cefixime in the Fasted and Fed State. Europ J Clin Pharmacol, 34:
525-528.
Faulkner RD, W Bohaychuk, RA Lanc, JD Haynes, RE Desjardins, A Yacobi and BM Silber,
1988a. Pharmacokinetics of Cefixime in the Young and Elderly. J Antimicrob Chemoth,
21(6): 787-794.
Faulkner RD, W Bohaychuk, RE Desjardins, ZM Look, JD Haynes, AI Weiss and BM Silber,
1987. Pharmacokinetics of Cefixime after Once-a-day and Twice-a-day Dosing to Steady
State. J Clin Pharmacol, 27(10): 807-812.
208
Faulkner RD, A Yacobi, JS Barone, SA Kaplan and BM Silber, 1987. Pharmacokinetic Profile of
Cefixime in Man. Pediatr Infect Dis J, 6(10): 963-970.
Finucane ML, S Paul, F James and AS Theresa, 2000. Gender, race, and perceived risk: The
'white male' effect. Health Risk and Soc, 2(2): 159-172.
Flesher BF, 1976. Effect of Changes in Dietary Components on the Serum Bilirubin in Gilbert’s
Syndrome. Am J Clin Nutr, 29: 705-709.
Fletcher CV, EP Acosta and JM Strykowski, 1994. Gender Differences in Human
Pharmacokinetics and Pharmacodynamics. J Adolescent Health, 15(8): 619-629.
Forsyth JS, JA Moreland and GW Rylance, 1 9 8 2 . The Effect of Fever on Antipyrine
Metabolism in Children. Brit J Clin Pharmacol, 13: 811-815.
Foster TS, 1991. Selecting Therapeutically Equivalent Products: Special Cases, Am pharm NS
31(11): 49-54.
Francis P, MD Tally, E Robert, MD Desjardins, F Eugene, BS McCarthy and C Kenneth,
1987. Safety Profile of Cefixime. Pediatr Infect Dis J, 6: 976-980.
Fuchs PC, RN Jones, AL Bamy, C Thomsberry, LW Ayers and E Cavan, 1 9 8 6 . In Vitro
Evaluation of Cefixime (FK027, FRl 7027, CL284, 635): Spectrum Against Recent
Clinical Isolates, Comparative Antimicrobial Activity, Β- Lactamaes Stability, and
Preliminary Susceptibility Testing Criteria. Diagnostic. Microb Infect Dis, 5: 151-162.
Fujii A, N Yasui-Furukori, T Nakagami, T Niioka, M Saito, Y Sato and S Kaneko, 2009.
Comparative In Vivo Bioequivalence and In Vitro Dissolution of Two Valproic Acid
Sustained Release Formulations. Drug Des Devel Ther, 2: 139-144.
Fujii R, 1986. Pharmacokinetics and Clinical Studies of FK027 in the Pediatrics Field in a Review of
New Oral Cephalosporins. Edited by: R.C. Moellering, Jr., K. Shima. Univ. Tokyo press,
Tokyo. pp. 71-75.
Gandhi M, F Aweeka and RM Greenblatt, 2004. Sex Differences in Pharmacokinetics and
Pharmacodynamics. Annu Rev Pharmacol, 44: 499-523.
Gandhi SP and SJ Rajput, 2009. Study of Degradation Profile and Development of Stability
Indicating Methods for Cefixime Trihydrate. Indian J Pharm Sci, 71(4): 438-442.
209
Garg SK, RK Chaudhary and AK Srivastava, 1992. Disposition Kinetics and Dosage of
Cephalexin in Cow Calves following Intramuscular Administration. Ann Rech Vet, 23:
399-402.
Gibaldi M and D Perrier, 1982. Pharmacokinetics. 2nd ed, New York: Marcel Dekker.
Gibaldi M, 1984. Biopharmaceutics and Clinical Pharmacokinetics. Lea and Fabiger 600
Washington Square Philadephia, U.S.A.
Gibaldo M, 1977. Biopharmaceutics and Clinical Pharmacokinetics. Lea and Febiger,
Philadelphia.
Girgis NI, DR Tribble and Y Sultan, 1995b. Short Course Chemotherapy with Cefixime in
Children with Multidrug-Resistant Salmonella Typhi Septicaemia. J Trop Pediatrics, 41:
364-365.
Girgis NI, Y Sultan, O Hammad and Z Fand, 1995a. Comparison of the Efficacy, Safety and Cost
of Cefixime, Ceftriaxone and Aztreonam in the Treatment of Multidrug-Resistant
Salmonella Typhi Septicemia in Children. J Trop Pediatrics, 14: 603-605.
Gohil PV, UD Patel, SK Bhavsar, and AM Thaker, 2009. Pharmacokinetics of Ceftriaxone in
Buffalo Calves (Bubalus bubalis) following Intravenous and Intramuscular
Administration. Iran J Vet Res, 10(1): 33-37.
Golcu A, B Dogan and SA Ozkan, 2005. Anodic Voltammetric Behavior and Determination of
Cefixime in Pharmaceutical Dosage Forms and Biological Fluids. Talanta, 67(4): 703-
712.
Gollan GL, C Bateman and BH Billing, 1 9 7 6 . Effect of Dietary Composition on the
Unconjugated Hyperbilirubinemia of Gillert’s Syndrome. Gut, 17: 335-340.
Gonik B, S Feldman, LK Pickering and CG Doughtie, 1986. Pharmacokinetics of Cefoperazone
in the Parturient. Antimicrob agents Ch, 30(6): 874-876.
Gonzalez-Hernandez R, L Nuevas-Paz, L Soto-Mulet, M Lopez-Lopez and J Hoogmartens,
2001. Reversed Phase High Performance Liquid Chromatographic Determination of
Cefixime in Bulk Drugs. J Liq Chromatogr RT, 24(15): 2315-2324.
Goodman and Gillman’s, 1996, The Pharmacological Basis of Therapeutics. 9th Ed, Macmillan
Publishing Company, USA. pp: 1084-97.
210
Gorodischer R, J Krasner, JJ McDevitt, JP Nolan and SJ Yaffe, 1976. Hepatic Microsomal Drug
Metabolism after Administration of Endotoxine in Rats. Biochem Phamacol, 25(3):
351-353.
Goto S, F Ikeda, F Ogawa, S Myazaki and Y Kaneko, 1985. In Vitro and In Vivo Antibacterial
Activities of Cefixime, a New Oral Cephalosporin. Chemotherapy 33(6): 29-45.
Goudah A, MM Samar, S Jae-Han and AM Abd el-aty, 2006. Influence of Endotoxin Induced
Fever on the Pharmacokinetics of Intramuscularly Administered Cefepime in Rabbits. J
Vet Sci, 7(2): 151-155.
Goudah AM and M Sherifa, 2013. Pharmacokinetics and Distribution of Ceftazidime to Milk
after Intravenous and Intramuscular Administration to Lactating Female Dromedary
Camels (Camelus dromedarius). JAVMA, 243(3): 424-429.
Gouyon JB, A Pechinot, C Safran, P Chretien, D Sandre and A Kazmierczak, 1990.
Pharmacokinetics of Cefotaxime in Preterm Infants. Dev Pharmacol Ther, 14(1): 29-34.
Greenblatt DJ and LVM Lisa, 2008. Gender Has a Small but Statistically Significant Effect on
Clearance of CYP3A Substrate Drugs. J Clin Pharmaco, 48(11) 1350-1355.
Grellet J, L Couraud, MC Saux and G Roche, 1989. Pulmonary diffusion of cefixime in man. Presse
Med, 18: 1589-1592.
Gross JL, R Friedman, MJ Azevedo, SP Silveiro and M Pecis, 1992. Effect of Age and Sex on
Glomerular Filtration Rate Measured by 51Cr-EDTA. Braz J Med Biol Res, 25(2): 129-
134.
Guay DR, RC Meatherall, GK Harding and GR Brown, 1986. Pharmacokinetics of Cefixime
(CL 284,635; FK 027) in Healthy Subjects and Patients with Renal Insufficiency.
Antimicrob Agents Ch, 30(3): 485-490.
Guerrini VH, LJ Filippich, GR Cao, PB English and DWA Bourne, 1985. Pharmacokinetics of
Cefaronide, Ceftriaxone and Cefoperazone in Sheep. J Vet Pharmacol Ther, 8: 120-127.
Gugler R, JW Kurlen, CJ Jensen, U Klehr and J Hartlapp, 1 9 7 9 . Clofibrate Disposition in
Renal Failure and Acute Chronic Liver Disease. Europ J Clin Pharmacol, 15: 341 -347.
Gupta JK, KC Rakesh and KD Vinod, 2008. Pharmacokinetics after Single Intramuscular
Administration and In Vitro Plasma Protein Binding Of Cefoperazone in Cross Bred
Calves. Vet Arhiv, 78 (5): 441-448.
211
Gupta JK, RK Chaudhary and V Dumka, 2007. Cefoperazone Pharmacokinetics Following
Single Intravenous Administration in Cross Bred Calves. Isr J Vet Med, 62: 3-4.
Gupta SP, S Mehta S and B N S Walia, 1 9 7 0 . Small Bowel Function in Protein Calorie
Malnutrition. Indian Pediatr, 7: 481-488.
Hafeez M, 1985. Bioavailability of Ampicillin Following Intravenously, Intramuscularly and
Orally in Sheep. M. Sc. Thesis, University of Agriculture, Faisalabad. Pakistan.
Halkin H, M Lidji a n d E Rubinstein, 1 9 8 1 . The Influence of Endotoxin-Induced Pyrexia
on the Pharmacokinetics of Gentamicin in the Rabbit. J Pharmacol Exp Ther, 216: 415-
418.
Halperin-walega E, VK Batra, AP Tonelli, A Barr and A Yacobi, 1988. Disposition of Cefixime
in the Pregnant and Lactating Rat. Transfer to the Fetus and Nursing Pup. Drug Metab
Dispos, 16(1): 130-134.
Handsfield HH, MM Williams, WH Edward, MD John, MC Jean, SV Michael, AR Cindy, and
ME Josphine, 1991. A Comparison of Single-Dose Cefixime with Ceftriaxone as
Treatment for Uncomlicated Gonorrhea. New Engl J Med, 325(19): 1337-1341.
Haq MF, 1997. Manual of Drug Laws and Rules Formed There Under. National Law Times
Publications, Lahore, pp25.
Healy DP, JV Sahai, LP Sterling and EM Racht, 1989. Influence of an Antacid Containing
Aluminum and Magnesium on the Pharmacokinetics of Cefixime. Antimicrob Agents Ch,
11(33): 1994-1997.
Hedrick JA, 2010. Community-Acquired Upper Respiratory Tract Infections and the Role of
Third-Generation Oral Cephalosporins. Expert Rev Anti-Infec, 8(1): 15-21.
Hernández IG, JC Helgi and S Angela, 2008. Effect of Malnutrition on the Pharmacokinetics of
Cefuroxime Axetil in Young Rats. J Pharm Pharm Sci, 11(1): 9-21.
Homeida M, L Jackson and CJC Roberts, 1978. Decreased First-Pass Metabolism of Labetalol
in Chronic Liver Disease. BMJ-Brit Med J, 2: 1048-1050.
Homick RB, SE Greisman, TE Woodward, H L D u p o n t , A T D a w k i n s a n d M J S n y d e r ,
1 9 7 0 . Typhoid Fever: Pathogenesis and Immunologic Control. Ne w Engl J Med, 283: 686-
691.
212
Honda S, A Taga, K Kakehi, S Koda and Y Okamoto, 1992. Determination of Cefixime and its
Metabolites by High-Performance Capillary Electrophoresis. J Chromatogr A, 590(2):
364-368.
Hooton TM, C Johnson, C Winter, L Kuwamura, ME Rogers, PL Roberts and WE Stamm, 1991.
Single-Dose and Three-Day Regimens of Ofloxacin versus Trimethoprim-
Sulfamethoxazole for Acute Cystitis in Women. Antimicrob Agents Ch, 35: 1479-1483.
Huet PM and JP Villeneuve, 1 9 8 3 . Determinants of Drug Disposition in Patients with Cirrhosis.
Hepatology. 3: 913-918.
Hussain T, I Javed, F Muhammad and ZU Rahman, 2014. Disposition Kinetics of Enrofloxacin
following Intramuscular Administration in Goats. Pak Vet. J, 34(3): 279-282.
Irvani A, G Richards, D Johnson and A Bryant, 1 9 8 8 . A Double-Blind, Multicenter, Comparative
Study of the Safety and Efficacy of Cefixime versus Amoxicillin in the Treatment of Acute
Urinary Tract Infections in Adult Patients. Am J Med, 16(85): 17-23.
Iwai N, M Shibata, P Mizoguchi, H Nakamura and M Katayama, 1986 . Fundamental and Clinical
Studies on Cefixime in Pediatrics. Japn J Antibiot, 39: 1087-1105.
Jagadeensan V and Krishnaswamy K, 1985. Drug Binding in the Undernourished: A Study of Binding of
Propranolol to Alpha-I Acid Glycoprotein. Eur J Phamacol, 27: 657-659.
Jain R, VK Gupta, N Jadon and K Radhapyari, 2010. Voltammetric Determination of Cefixime
in Pharmaceuticals and Biological Fluids. Anal Biochem, 407(1): 79-88.
Javed I, 1998. Over Dosage of Livestock Drugs: a Big Wastage, Daily Dawn, September 4, 1998.
Javed I, M Nawaz and FH Khan, 2003. Pharmacokinetic and Optimal Dosage of Kanamycin in
Domestic Ruminant Species. Veterinarski Arhiv, 73(6): 323-331.
Javed I, Z Iqbal Z, ZU Rehman, MZ Khan, F Muhammad, FH Khan and JI Sultan, 2009b. Renal
Handling of Coproflxiacin in Domestic Ruminant Species. Turk J Vet Anim Sci, 33: 303-
310.
Javed I, Z Iqbal, ZU Rehman, FH Khan, F Muhammad, Z Iqbal and B Aslam, 2006. Renal
Clearance and Urinary Excretion of Kanamycin in Domestic Ruminant Species. Pak Vet
J, 26(1): 1-8.
Javed I, Z Iqbal, ZU Rehman, MZ Khan, F Muhamamd, B Aslam, MA Sadhu and JI Sultan,
2009a. Disposition Kinetics and Optimal Dosage of Ciprofloxacin in Healthy Domestic
Ruminant Species.Acta Vet Brno, 78: 155-165.
213
Jayatilaka N and G Kinghorn, 2006. Recommended management of common STIs in primary
care. Prescriber, 17(21): 29-41.
Jieying H, M Huang and X Zhao, 1996. Comparative Study on Pharmacokinetics in Volunteers
of Domestic and Imported Cefixime in 3 Dosage Forms. Chinese New Drugs J. 6(4): 48-
53.
Johnson JR and WE Stamm, 1989. Urinary Tract Infections in Women. Diagnosis and
Treatment. Ann Intern Med, 111: 906-917.
Joshi B and KH Suresh, 2009. The Pharmacokinetics of Cefepime in E. Coli Lipopolysaccharide
Induced Febrile Buffalo Calves. Vet Arhiv, 79 (6): 523-530.
Jovanovic SE, D Agbaba, D Zivanov-Stakic and S Vladimirov, 1998. HPTLC Determination of
Ceftriaxone, Cefixime and Cefotaxime in Dosage Forms. J Pharmceut Biomed, 18 (4-5):
893-898.
Juchau MR, ST Chao a nd CJ Omiecinski, 1980. Drug Metabolism by the Human Fetus. Clin
Pharmacokinet, 5: 320-339.
Jusko WJ and M Gretch, 1 9 7 6 . Plasma and Tissue Protein Binding of Drugs in
Pharmacokinetics. Drug Metab Rev, 5: 43-140.
Kalman D and LB Steven, 1990. Review of the Pharmacology, Pharmacokinetics and Clinical
Use of Cephalosporins. Tex Heart I J, 17(3): 203-215.
Kando JC, KA Yonkers and JO Cole, 1995. Gender as a Risk Factor for Adverse Events to
Medications. Drugs, 50: 1-6.
Kang YS, SY Lee SY, NH Kim, HM Choi, JS Park, W Kim and HJ Lee, 2006. A Specific and
Rapid HPLC Assay for the Determination of Cefroxadine in Human Plasma and its
Application to Pharmacokinetic Study in Korean. J Pharmaceut Biomed, 40(2): 369-374.
Karchmer AW, 1995. Cephalosporins in Mandell, Do-adlas, and Bannee’s Principles and Practice
of Infectious Diseases, 4th
Ed. (Mandell, G.l. Bennett, J. E, and Dolin. R., Eds) Churchill
Livingstone, Inc, New York. pp. 247-63.
Kathiresan K, R Murugan, MS Hameed, KG Inimai and T Kanyadhara, 2009. Analytical Method
Development and Validation of Cefixime and Dicloxacillin Tablets by RP-HPLC.
Rasayan J Chem, 2(3): 588-592.
Kato Y, K Kuge and H Kusuhara, 2002. Gender Difference in the Urinary Excretion of Organic
Anions in Rats. J Pharmacol Exp Ther, 302(2): 483-489.
214
Kaza M, L Andrzej, SB Krystyna, K Hanna, JR Piotr, G Piotr, D Tomasz, G Anna, T Andrzej,
PC Ewa, SS Malgorzata and W Ewa, 2012. Bioequivalence Study of 500 Mg Cefuroxime
Axetil Film-Coated Tablets in Healthy Volunteers. Acta Pol Pharm, 69(6): 1356-1363.
Kearns GL, B Hillman and JT Wilson, 1 9 8 2 . Dosing Implications of Gentamicin Disposition in
Patients with Cystic Fibrosis. J Pediatr, 100: 312-318.
Kees and Naber, 1990. Pharmacokinetics of Cefixime in Volunteers and a Literature Comparison
with the New Ester Prodrug Cephalosporins. Infection. 18 (3): 150-154.
Kees F, KG Naber, G Sig, W Ungethum and H Grobecker, 1990. Relative Bioavailability of
Three Cefixime Formulations. Arzneimittelforschung. 40(3): 293-297.
Kelly HB, R Menendez, L Fan and S Murphy, 1982. Pharmacokinetics of Tobramycin in Cystic
Fibrosis. J Pediatr, 100: 318-321.
Khandagle KS, SV Gandhi, PB Deshpande and NV Gaikwad, 2011. A Simple and Sensitive
RPHPLC Method for Simultaneous Estimation of Cefixime and Ofloxacin in Combined
Tablet Dosage Form. Int J Pharm Pharm Sci, 3(1): 46-48.
Khandagle KS, SV Gandhi, PB Deshpande, AN Kale and PR Deshmukh, 2010. High
Performance Thin Layer Chromatographic Determination of Cefixime and Ofloxacin in
Combined Tablet Dosage Form. J Chem Pharm Res, 2(5): 92-96.
Khon LT, 2000. Organizing and Managing Care in a Chang-ing Health System. Health Serv Res,
35(1): 37-52.
Kiani R, D Johns, B Nelson and EF McCarthy, 1988. Comparative Multicenter Studies of Cefixime
and Amoxicillin in the Treatment of Respiratory Tract Infections. Am J Med, 85(3): 6-13.
Kitamori N, S Kawajiri and T Matsuzawa, 1976. The Particle Size Evaluation of Parenteral
Suspensions of Chloramphenicol and Correlation of Particle Size to Plasma Levels.
Chem Pharm Bull, 24(11): 2597-2602.
Klepser ME, MN Marangos, KB Patel, DP Nicolaus, R Quintiliani and CH Nightingale, 1995.
Clinical Pharmacokinetics of Newer Cephalosporins. Clin Pharmacokinet, 28: 361-384.
Klotz U, GR Avant, A Hoyumpa, S Schenker and GR Wilkinson, 1 9 7 5 . The Effect of Age and
Liver Disease on The Disposition and Elimination of Diazepam in Adult’s Man. J Clin Invest,
55: 347-359.
215
Knapp CC, J Sierra-Madero and JA Washington, 1988. Antibacterial Activities of Cefpodoxime,
Cefixime, and Ceftriaxone. Antimicrob Agents Chemother, 32(12): 1896-1898.
Kokwaro GO, AP Glacier and SP Ward, 1 9 3 3 a . Effect of Malaria Infection and Endotoxin-
Induced Fever on Phenacetin O-Deethylation by Rat Liver Microsoms. Biochem Phamacol,
45(6): 1235-1241.
Kokwaro GO, ISP Szwandl and AP Glacier, 1 9 9 3 c . Metabolism of Caffeine and Theophylline
in Rats with Malaria a nd Endotox-Induce Fever. Xenobiotica, 23: 1391-1397.
Kokwaro GO, S Isamil and AP Glacier, 1993b. Effect of Malaria Infection and Endtoxin-Induce
Fever on the Metabolism of Antipyrine and Metronidazole in the Rat. Biochem Pharmacol, 45:
1243-1249.
Kraus JW, PV Desmond and JP Marshall, 1 9 7 8 . Effect of Aging and Liver Disease on
Disposition of Lorazepam. Clin Pharmacol Ther, 24: 411-419.
Krebs NF, 2001. Bioavailability of Nutrients and other Bioactive Components from Dietary
Supplements. J Nutr, 131: 1351S–1354S.
Krishnaswamy K, 1978. Drug Metabolism and Pharmacokinetics in Malnutrition. Clin Pharmacokinet,
3: 216-240.
Krishnaswamy K, 1987. Effects of Malnutrition Drug on Metabolism and Toxicity in Humans. In
Hath Cock J.N. (Ed). Nutritional Toxicology: Academic press, Inc., New York, USA, pp:
105-128.
Krishnaswamy K, V Ushasri and A N Naidu, 1981. The Effect of Malnutrition on the
Pharmacokinetics of Phenylbulazone. Clin Pharamacokinet, 6: 152-159.
Kudo N, M Katakura and YI Sato, 2002. Sex Hormone Regulated Renal Transport of
Perfluorooctanoic Acid. Chem Biol Interact, 139(3): 301-316.
Kumar R, P Singh and H Singh, 2011. Development of Colorimetric Method for the Analysis of
Pharmaceutical Formulation Containing Both Ofloxacin and Cefixime. Int J Pharm
Pharm Sci, 3(2): 178-179.
Kumari HBV, S Nagarathna and A Chandramuki, 2007. Antimicrobial Resistance Pattern among
Aerobic Gram-Negative Bacilli of Lower Respiratory Tract Specimens of Intensive Care
Unit Patients in a Neurocentre. Indian J Chest Dis Allied Sci, 49(1): 19-22.
216
Kumudhavalli MV, S Sahu, K Abhiteja and B Jayakar, 2010. Development and Validation of
RP-HPLC Method for Simultaneous Determination of Cefixime and Potassium
Clavulanate in Tablet Dosage Form. Int J Pharma Recent Res, 2(2): 57-60.
Kurashige T, H Morita, K Araki, H Oguara, N Mroika and I Kitamura, 1986. Fundamental and
Clinical Studies on Cefixime in Pediatrics. Japn J Antibiot, 39: 1157-1165.
Kwon Y, 2001. Handbook of Essential Pharmacokinetics, Pharmacodynamics, and Drug
Metabolism for Industrial Scientists. Kluwer Academic/Plenum Publishers, New York,
NY.
Lakshmi R, S Anitha, KN Anila and PR Roshni, 2012.Warfarin Resistance–Mechanisms and
Management. IJPSR, 3(2): 353-357.
Lan-Ying Y, J Zhang, Y Liu and B Wang, 2004. Study on Bioavailability and Bioequivalence of
Cefixime Tablets in Healthy Volunteers. J Pharmceut Biomed, 3(2): 14-22.
Lavicky J, J Cerny, L Celeda, J Rotta, J Kvetina, H Raskova and A Kubicek, 1986. Changes of
Phamacokinetics of Trimethoprim after Pretreament with Streptococcal Peptidoglycan. Eu r
J Drug Metab Ph, 11: 17-22.
Leenen FH and AS Van- Miert, 1 9 6 9 . Inhibition of Gastric Secretion by Bacterial Lip
Polysaccharide in the Rat. Eur J Pharmacol, 8: 228-231.
Leggett NJ, C Caravaggio and MJ Rybak, 1990. Cefixime. DICP. 24(5): 489-95.
Lei Z, WA Dong, ZS Qi, TL Ping and WU Yin, 2003. Relative bioequivalence and
pharmacokinetics of Cefixime capsules in healthy volunteers. Journal of the Fourth
Military Medical University, 2003-07.
Leroy A, B Oser, P Grise and G Humbert, 1995. Cefixime Penetration in Human Renal
Parenchyma. Antimicrob Agents Ch, 39(6): 1240-1242.
Leszczynska A, 1979. The Effect of Pyrogen Induced. Fever on Pharmacokinetics of Rifamycin. S.V. Pol
J Pharmacol Phram, 31: 19-24.
Levison ME and JH Levison, 2009. Pharmacokinetics and Pharmacodynamics of Antibacterial
Agents. Infect Dis Clin North Am, 23(4): 1-29.
Levy G, NW Khanna, DM Soda, O Tsuzuki O and L Stem, 1975. Pharmacokinetics of
Acetaminophen in the Human Neonates: Formation of Acetaminophen Sulfate In
217
Relation to Plasma Bilirubin Concentrations and D-Glucaric Acid Excretion. Pediatr. 55:
818-825.
Lewis GP and WJ Jusko, 1975 . Pharmacokinetics of Ampicillin in Cirrhosis. Clin Pharmacol
Ther, 18: 475-484.
Li M, MA Andrew, J Wang, DH Salinger, P Vicini, RW Grady, B Phillips, DD Shen and GD
Andeson, 2009. Effects of Cranberry Juice on Pharmacokinetics of Beta-Lactam
Antibiotics Following Oral Administration. Antimicrob Agents Ch, 53(7): 2725-2732.
Lippincott W and Wilkins, 1996. Drug Watch. Reviewed Work: The Am J Nurs, 96(7): 52.
Reviewed from Source, 1996: Ann. Pharmacother. 30: 228-232.
Liu P, M Markus, G Maria, O Bernd and D Hartmut, 2005. Tissue Penetration of Cefpodoxime
and Cefixime in Healthy Subjects. J Clin Pharmacol, 45: 564-569.
Liu P, M Muller, M Grant, AI Webb, B Obermann and H Darendorf, 2002. Interstitial Tissue
Concentrations of Cefpodoxime. J Antimicrob Chemoth, 50: 19-22.
Liu XD, L Xie, JP Gao, LS Lai and GQ Liu, 2007. Cefixime Absorption Kinetics after oral
Administration to Humans.
Lode H, 1988. Drug Interactions with Quinolones. Rev Infect, 10(1): 132-136.
Lodise TP, R Pypstra, JB Kahn, BP Murthy, HC Kimko, K Bush, GJ Noel and GL Drusano,
2007. Probability of Target Attainment for Ceftobiprole As Derived From a Population
Pharmacokinetic Analysis of 150 Subjects. Antimicrob Agents Ch, 51(7): 2378-2387.
Low DE, 1995. Assessment of the Use of Cefixime for Switch Therapy. Infection, 23: 91-94.
Lumbiganon P, K Pengsaa and T Sookpranee, 1 9 9 1 . Ciprofloxacin in Neonates and Its
Possible Adverse Effect on the Teeth. Pediatr Infect Dis J, 10: 619-620.
M Prades, MP Brown, R Gronwall and NS Miles, 1988. Pharmacokinetics of Sodium Cephapirin
in Lactating Dairy Cows. Am J Vet Res, 49(11): 1888-90.
Macfarlane WV, 1961. Aust. J. Agr. Res., 12: 889-912.
Maeda H, M Sako, A Fujii, H Yamazaki, G Kawabata, M Harada, S Arakawa, K Umezu, S
Kamidono and J Ishigami, 1986. Pharmacokinetics of Cefixime in Patients with Impaired
Renal Function. Jpn J Antibiot, 39(10): 2716-2720.
Maggio RM, PM Castellano and TS Kaufman, 2008. A New Principal Component Analysis Based
Approach for Testing Similarity of Drug Dissolution Profiles. Eur J Pharm Sci, 34: 66-77.
218
Maheshwari RK, S Moondra, M More, SP Prajapati and S Verma, 2010. Quantitative
Spectrophotometric Determination of Cefixime Tablet Formulation Using Sodium
Tartarate as Hydrotropic Solubilizing Agent. Int J Pharm Tech, 2 (3): 828-836.
Majid A, 2014. Renal Clearance and Urinary Excretion of Cefixime in healthy male subjects.
M.Phil. Thesis, Department of Physiology and Pharmacology, University of Agriculture,
Faisalabad, Pakistan.
Makoid MC, PJ Vuchetich and UV Banakar, 1996. Bioavailability, Bioequivalence, and Drug
Selection. In: Basic Pharmacokinetics 1st ed, The Virtual University Press. pp. 59-102.
Malik MS, I Iqbal and WA Rabbani, 1998. Comparative Study of Cefixime and Chloramphenicol
in Children with Typhoid Fever. J Pak Med Assoc, 18: I06-107.
Mamzoridi K, N Kasteridou, A Peonides and I Niopas, 1 9 9 6 . Pharmacokinetics of Cefixime in
Children with Urinary Tract Infection after a Single Oral Dose. Pharmacol Toxicol, 78:
417-420.
Martin C, V Xavier, A Majed, L Francois, E Karim, S Rachid and P Michele, 1996. Penetration
of Ceftriaxone (1 Or 2 Grams Intravenously) Into Mediastinal and Cardiac Tissues in
Humans. Antimicrob Agents Ch, 40 (3): 812-815.
Martindale, 2009. The Complete Drug Reference. 36th Ed, London, Pharmaceutical Press, pp:
225.
Mathe A, K Kinga, F Monika, S Dora, A Piroska and R Ferenc, 2006. The Effect of Different
Doses of Cisplatin on the Pharmacokinetic Parameters of Cefepime in Mice. Lab Anim,
40: 296-300.
McAteer JA, MF Hiltke, BM Silber and RD Faulkner, 1987. Liquid Chromatographic
Determination of Five Orally Active Cephalosporins-Cefixime, Cefaclor, Cefadroxil,
Cephalexin and Cephradin in Human Serum. Clin Chem, 33(10): 1788-1790.
Mehta S, 1983. Drug Disposition in Children with Protein Energy Malnutrition. J Pediatr Gastr Nutr, 2:
407-417.
Mehta S, 1990. Malnutrition and Drugs Clinical Implications. Dev Pharmacol Ther, 15(34): 159-165.
Mehta S, CK Nain, D Yadav, B Sharma and VS Mathur, 1 9 8 5 . Disposition of
Acetaminophen in Children with Protein Calorie Malnutrition. Inter J Clin Pharmacol
Therap Toxicol, 23: 3 l l -315.
219
Meibohm B, I Beierle and H Derendorf, 2002. How Important Are Gender Differences In
Pharmacokinetics. Clin Pharmacokinet, 41(5): 329-342.
Memon IA, AG Billoo and HI Memon, 1997. Cefixime: An Oral Option for the Treatment of
Multidrug-Resistant Enteric Fever in Children. South Med J, 90: 1204-1207.
Meng F, X Chen, Y Zeng and D Zhong, 2005. Sensitive Liquid Chromatography-Tandem Mass
Spectrometry Method for the Determination of Cefixime in Human Plasma: Application
to a Pharmacokinetic Study. J Chromatogr, 819(2): 277-282.
Merry DJ, L Riva and D G Poplack, 1 9 9 8 . Impact of Nutrition on Pharmacokinetics of
Anti-Neoplastic Agents Int J Cancer, 11: 48-5 l.
Meyers BR, ES Srulevitch, J Jacobson and SZ Hirschman, 1983. Crossover Study of the
Pharmacokinetics of Ceftriaxone Administered Intravenously or Intramuscularly to
Healthy Volunteers. Antimicrob Agents and Chemoth, 24(5): 812-814.
Miller B, E Hershberger, D Benziger, M Trinh, and I Friedlanda, 2012. Pharmacokinetics and
Safety of Intravenous Ceftolozane Tazobactam in Healthy Adult Subjects following
Single and Multiple Ascending Doses. Antimicrobial Agents Ch, 56(6): 3086-3091.
Miller JM, 1997. Open Study of the Safety and Efficacy of a Single Oral Dose of Cefixime for
the Treatment of Gonorrhea in Pregnancy. Infec Diseases Obstet Gynecol, 5: 259-261.
Miller SW and JG Storm, 1990. Drug Product Selection: Implications for the Geriatric Patient.
The Consultant Pharmacist, 5(1): 30-37.
Ming-hui L, 2009. Comparison of Relative Bioavailability between Disintegration Tablets and
Capsules of Cefixime in Healthy Volunteers. Herald of Medicine, 28(6): 702-704.
Min-ji W, LV Yuan, K Zi-sheng, Z Pu, L Yan and LI Tian-yun, 2004. Pharmacokinetics and
Bioequivalence Study of Cefixime Tablet in Healthy Volunteers. The Chin J Clin Pharm,
2004-01.
Mircioiu I, A Aldea, A Valentina, N Olimpia, M Dalia, F Radulescu and F Enache, 2007.
Internal Standard versus External Standard in Bioanalytical Assay for Bioequivalence
Studies. Farmacia, 5: 569-579.
Miyazaki M, K Kida, H Matsuda and M Murase, 1 9 8 6 . Fundamental and Clinical Studies on
Cefixime in Pediatric Field. Japn J Antibiot, 39: 1166-1175.
220
Moffat A., Osselton M. and Widdop B, 2011. Clarke.s Analysis of Drugs and Poisons in
pharmaceuticals, body fluids and postmortem material. 4th Ed. London. Pharmaceutical
Press.
Mohamed SS, AM Mohamed, AA Eltahir, AA Nemat, AA Zoheir and AA Abdulazim, 2011.
Comparative Pharmacokinetics and Bioequivalence Studies of Three Oral Cephalexin
Monohydrate Formulations. Jordan J Pharm Sci, 4(2): 89-96.
Monfrinotti A, l Ambros, AP Prados, V Kreil and M Rebuelto, 2009. Pharmacokinetics of
Ceftazidime after Intravenous, Intramuscular and Subcutaneous Administration to Dogs.
J Vet Pharmacol Ther, 33: 204-207.
Montay G, AL Liboux, JJ Thebault, G Roche, A Frydman and J Gaillot, 1989. Pharmacokinetics
of Cefixime in Healthy Volunteers after a Single Oral Administration of 200 Mg. Presse
Med, 18(32): 1583-1586.
Montay G, F Masala, Y Le-Roux, A Le-Liboux, J Uhlrich, D Chassard, JJ Thebault, G Roche and
A Frydman, 1991. Comparative Bioavailability Study of Cefixime Administered as
Tablets or Aqueous Solution. Pharmacol Res, 12(5): 64-77.
Moorthi K, G Fleckenstein and B Nies, 1990. Concentration of Cefixime in Bile, Gallbladder
Wall and Serum after Preoperative Administration in Patients Undergoing
Cholecystectomy. Methods Find Exp Clin Pharmacol, 12(4): 287-90.
Morselli PL, 1976. Clinical Pharmacokinetics in Neonates. Clin Pharmacokinet, 1: 8l-91.
Morselli PL, R Franco-Morselli and L Bossi, 1980. Clinical Pharmacokinetics in New Borns and Infants:
Age-Related Differences and Therapeutic Implications. Clin Pharmacokinet. 5: 485-
527.Motohiro T., Tanaka K., Koga T., Shimada Y., Tomita S., Nishiyama T., lshimoto
Motohiro T, K Tanaka, T Koga, Y Shimada, S Tomita, T Nishiyama, K Ishimoto, K Tominaga,
F Yamashita and K Nagayama, 1986. Pharmacokinetics and Clinical Effects of Cefixime
in Pediatrics. Jpn J Antibiot, 39(4): 1177-1200.
Muhammad F, 1997. Disposition Kinetics, Renal Clearance and Urinary Excretion of
Kanamycin in Mules. M.Sc. Thesis, Department of Physiology and Pharmacology,
University of Agriculture, Faisalabad, Pakistan.
Mulhall A, J De-Louvois and J James, 1985. Pharmacokinetics and Safety of Ceftriaxone in
Neonate. European J Pediatrics, 144(4): 379-82.
221
Nahata MC, VM Kohlbrenner and WJ Barson, 1993 . Pharmacokinetics and Cerebrospinal Fluid
Concentration of Cefixime in Infants and Young Children. J Chemotherapy, 39: 1-5.
Nakashima M, T Uematsu, Y Takiguchi and M Kanamaru, 1987. Phase I Study Of Cefixime, A
New Oral Cephalosporin. J Clin Pharmacol, 27(5): 425-431.
Nanda RK, J Gaikwad and A Prakash, 2009a. Simultaneous Spectrophotometric Estimation of
Cefixime and Ornidazole in Tablet Dosage Form. Int J Pharm Tech Res, 1(3): 488-491.
Nanda RK, J Gaikwad J and A Prakash, 2009b. Estimation of Cefixime and Ornidazole in its
Pharmaceutical Dosage Form by Spectrophotometric Method. J Pharm Res, 2(7): 1264-
1266.
Naqvi I, AR Saleemi and S Naveed, 2011. Cefixime: A Drug as Efficient Corrosion Inhibitor for
Mild Steel in Acidic Media, Electrochemical and Thermodynamic Studies. Int J
Electrochem Sc, 6: 146-161.
Naqvi SH, ZA Bhutta and BJ Farooqui, 1992. Therapy of Multidrug Resistant Typhoid in 58
Children. Scand J Infect Dis, 24: 175-179.
Narang AP, DV Datta and VS Mathur, 1985. Impairment of Drug Elimination in Patients with
Liver Disease. Int J Clin Pharmacol Ther Toxicol, 23: 28-32.
Natesan S, R Loganathan, V Krishnaswami and A Sugumaran, 2011. Simultaneous Estimation of
Cefixime and Ofloxacin in Tablet Dosage Form by RP-HPLC. Int J Res Pharm Sci, 2(2):
219-224.
Navaneeth BV and MR Belwadi, 2002. Antibiotic Resistance among Gram-Negative Bacteria of
Lower Respiratory Tract Secretions in Hospitalized Patients. Indian J Chest Dis Allied
Sci, 44(3): 173-176 .
Navolekar A, M Chaudhari, S Bhave and A Pandit, 1992. Ciprofloxacin Typhoid Fever. Indian J
Pediatr, 58: 335-339.
Nawaz M and BH Shah, 1985. Geonetical Considerations in the Quality Assurance of
Pharmaceuticals. Proc. Int. Seminar on Policies, Management and Quality Assurance of
Pharmaceuticals. Ministry of Health, Pakistan.
Nawaz M, 1982. Factors Affecting Disposition Kinetics of Sulfadimidine in Animals. Proc. 2nd
Cong Europ Assoc Vet Pharmacol Toxicol, 13-17, Sept. Toulouse, Pharmacologie and
Toxiclogoie, Veterinaires. INRA Publication, Paris, France. pp. 193-194.
222
Nawaz M, 1994. Geonetical Factors Affecting Biodisposition of Drugs. Canad J Physiol
Pharmacol Int Cong, Pharmacol, Montreal, Canada. Abst: pp: 12.2.57, XII.
Nawaz M, Hafeez, FH Khan, R Nawaz and T Iqbal, 1989. Bioavailability, Disposition Kinetics
and Renal Clearance of Ampicillin Following Three Routes of Administration in Sheep. J
Vet Med Assoc, 36: 84-89.
Nawaz M., Iqbal T. and Nawaz R, 1988. Geonetical Considerations in Disposition Kinetics
Evaluation of Chemotherapeutic Agents Vet. Pharmacol. Toxicol. & Therapy in Food
Producing Animals. Vol. 2, p-260, Proc. 4th Cong. Europ. Assoc. Pharmacol. Therap.,
28th August-2nd September (1988) Budapest.
Neal EA, PJ Meffin and PB Gregory, 1 9 7 9 . Enhanced Bioavailability and Decreased
Clearance of Analgesics in Patients with Cirrhosis. Gastroenterology, 77: 96-102.
Nerurkar R, M Ashish, A Ruchi, A Shalmali, G Samanta and S Arun, 2013. Cefixime in
Treatment of Upper Respiratory Tract Infection. IJORIM, 2(4): 95-99.
Neu HC, 1988. Pharmacokinetic and Clinical Studies of Cefixime: A World Wild Review.
Chemotherapy, 4: 531-533.
Nies BA, 1989. Comparative Activity of Cefixime and Cefaclor in an in Vitro Model Stimulating
Human Pharmacokinetics. Eur J Clin Microbiol Infect Dis, 8: 558-561.
Nisar I, 2014. Renal Clearance and Urinary Excretion of Cefixime in Healthy Female Subjects.
M.Phil. Thesis, Department of Physiology and Pharmacology, University of Agriculture,
Faisalabad, Pakistan.
Norrby SR, 1990. Short-Term Treatment of Uncomplicated Lower Urinary Tract Infections in
Women. Rev Infect Dis, 12: 458-467.
Okuno H, Y Kitao, M Takasu, H Kano, K Kunieda, T Seki, Y Shiozaki and Y Samcshima, 1 9 9 0 .
Depression of Drug Metabolizing Activity in the Human Liver by Interferon Alpha. Eur J Clin
Pharmacol, 39: 365-367.
Paintaud G, Y Bechtel, JPB Miguet and PR Bechtel, 1 9 9 6 . Effects of Liver Disease on Drug
Metabolism. Therapie, 51: 384-389.
Parada and Aguilera, 2007. Food Microstructure Affects the Bioavailability of Several Nutrients.
J Food Sci, 72(2): R21-R32.
223
Pareek V, SR Tambe and SB Bhalerao, 2010. Role of Different Hydrotropic Agents in
Spectrophotometric and Chromatographic Estimation of Cefixime. J Int Pharma BioSci,
1(3): 1-10.
Parveen G, 1982. Dehydration Effect on Pharmacokinetics of Chloramphenicol and Invitro
Invivo Evaluation of Commercial Suspensions. M. Sc. Thesis, Department of
Pharmaceutics, University of Karachi, Pakistan.
Pasha K, CS Patil, K Vijaykumar, S Ali and VB Chimkod, 2010. Reverse Phase HPLC Method
For the Determination of Cefixime in Pharmaceutical Dosage Forms. Res J Pharm Biol
Chem Sci, 1(3): 226-230.
Patel IH, JG Sugihara, RE Weinfeld, EGC Wong, AW Siemsen and SJ Berman, 1984.
Ceftriaxone Pharmacokinetics in Patients with Various Degrees of Renal Impairment.
Antimicrob Agents Ch, 25(4): 438-442.
Patel IH, RE Weinfeld, J Konikoff and M Parsonnet, 1982. Pharmacokinetics and Tolerance of
Ceftriaxone in Humans after Single-Dose Intramuscular Administration in Water and
Lidocaine Diluents. Antimicrob Agents Ch, 21(6): 957-962.
Patel PN, UD Patel, SHK Bhavsar and AMF Thaker, 2010. Pharmacokinetics of Cefepime
Following Intravenous and Intramuscular Administration in Sheep. IJPT, 9(1): 7-10.
Patel UD, KB Shailesh and MT Aswin, 2006. Pharmacokinetics and Dosage Regimen of
Cefepime Following Single Dose Intravenous Administration in Calves. IJPT, 5(2): 127-
130.
Patel UD, KZ Patani, SK Bhavsar and AM Thaker, 2006b. Disposition Kinetics of Cefepime
following Single Dose Intramuscular Administration in Calves. Int J Cow Sci, 2(1): 49-
51.
Patni KZ, UD Patel, SK Bhavsar, AM Thaker and J Sarvaiya, 2008. Single Dose
Pharmacokinetics of Cefepime after Intravenous and Intramuscular Administration in
Goats. Turk J Vet Anim Sci, 32: 159-162.
Pennington JE, DC Dale and HY Reynolds, 1 9 7 5 . Gentamicin Sulfate Phamacokinetics: Lower
Levels of Gentamicin in Blood during Fever. J Infect Dis, 132: 270-275.
Peter JVS, TB Marie, SH George, SK Judy, ES Bruce and EH Charles, 1992. Disposition of
Cefpodoxime Proxetil in Healthy Volunteers and Patients with Impaired Renal Function.
Antimicrob Agents Ch, 36(1): 126-131.
224
Petz LD, 1978. Immunological Cross-Reactivity between Penicillins and Cephalosporins.
J Infect Dis, 137: 74-79.
Pfeffer M, A Jackson, J Ximene and DM Perche, 1 9 8 7 . Comparative Human Oral Clinical
Phannacology of Cefadroxil, Cephalexin and Cephradine. Antimicrob Agents Ch, 11: 331-
338.
Pigoli G, RM Dorizzi and F Ferrari, 2010. Variations of the Urinary pH Values in a Population
of 13.000 Patients Addressing to the National Health System. Minerva Ginecol. 62(2):
85-90.
Pisarev VV, KV Zaitseva, LB Smirnova, VG Belolipetskaia, DA Kibalchich and IE Koltunov,
2009. Determination of Cefixime Blood Plasma Levels by HPLC. Antibiot Chemother,
54 (7-8): 37-40.
Pletz MWR, M Rau, J Bulitta, AD Roux, O Burkhardt, G Kruse, M Kurowski, CE Nord and H
Lode, 2004. Ertapenem Pharmacokinetics and Impact on Intestinal Microflora, in
Comparison to Those of Ceftriaxone, after Multiple Dosing in Male and Female
Volunteers. Antimicrob Agents Ch, 48 (10): 3765-3772.
Pleym H, O Spigset and ED Kharasch, 2003. Gender Differences in Drug Effects: Implications
for Anesthesiologists. Acta Anesth Scand, 47(3): 241-259.
Polasa K, KJR Murthy and K Krishnaashwamy, 1 9 8 4 . Rifampicin Kinetics in Under Nutrition.
Brit J Clin Pharmacol, 17: 481-484.
Preisig R, JG Rankin and J Sweating, 1966. Hepatic Hemodynamics during Viral Hepatitis in Man.
Circulation, 24: 188-197.
Prescott MA and JD Baggot, 1988. Antimicrobial Therapy in Veterinary Medicine, Blackwell
Scientific Publications, London.
Prince RA, JA Johnson and MM Weinberger, 1989. Influence Indotoxin-Induce Fever on the
Pharmscokinetics of Theophylline in the Rabbit Model. Pharmacotherapy, 9: 240-244.
Pussard E, H Barennes, H Daouda, F Clavier, AM Sant, M Dsse, G Granic and P Verdier, 1999. Quinine
Disposition in Globally Malnourished Children with Cerebral Malaria. Clin Pharmacol Ther, 65:
500-510.
Quintiliani R, 1996. Cefixime in the Treatment of Patients with Lower Respiratory Tract
Infections: Results of US Clinical Trials. Clin Ther, 18(3): 373–390.
225
Rabbani MW, L lqbal and MSA Malik, 1 9 9 8 . Comparative Study of Cefixime and
Chloramphenicol in Children with Typhoid Fever. J Pak Med Assoc, 48: 163-164.
Raghuram TC and K Krishnaswamy, 1981. Tetracycline Kinetics in Undernourished Subjects. Inter
J Clin Pharmacol Ther and Toxicol, 19: 409-413.
Raj KA, DI Yada, D Yada, C Prabu and S Manikantan, 2010. Determination of Cefixime
Trihydrate and Cefuroxime Axetil in Bulk Drug and Pharmaceutical Dosage Forms by
HPLC. Int J ChemTech Res, 2(1): 334-336.
Raj KA, 2010. Determination of Cefixime Trihydrate and Cefuroxime Axetil in Bulk Drug and
Pharmaceutical Dosage Forms by Electrophoretic Method. Int J ChemTech Res, 2(1):
337-340.
Rajput N, KD Vinod and SS Harpal, 2012. Disposition Kinetics and In Vitro Plasma Protein
Binding of Cefpirome in Cattle. Vet Arhiv, 82 (1): 1-9.
Rajput N, VK Dumka and HS Sandhu, 2007. Pharmacokinetics of Cefpirome in Buffalo Calves
(Bubalus Bubalis) Following Single Intramuscular Administration. Iran J Vet Res, 8(3):
212-217.
Rao J, K Sethy and S Yadav, 2011. Validated HPTLC Method for Simultaneous Quantitation of
Cefixime and Ofloxacin in Bulk Drug and In Pharmaceutical Formulation. Inter J
Compre Pharm, 2(4): 1-4.
Rao NGR, P Ram, U Kulkarni, 2010. Formulation and Evaluation of Gas Powered System of
Cefixime Tablets for Controlled Release Using Hydrophillic Polymers. IJRPBS, 1(2): 82-
91.
Rao S, 2005. Role of Cefexime in Paediatric UTI. IJPD. 1(4): 01-02
Rathinavel G, PB Mukherjee, J Valarmathy, L Samueljoshua, M Ganesh, T Sivakumar and T
Saravanan, 2008. A Validated RP-HPLC Method for Simultaneous Estimation of
Cefixime and Cloxacillin in Tablets. E-J Chem 5(3): 648-651.
Rathore MD, F Jacksonville, B Dhani and H Mumtaz, 1 9 9 6 . Multidrug-Resistant Salmonella
Typhi in Pakistani Children: Clinical Features and Treatment. South Med J, 89: 235-237.
Raz R, E Rottensterich, Y Leshem and H Tabenkin, 1994. Double-Blind Study Comparing 3-
Day Regimens of Cefixime and Ofloxacin in Treatment of Uncomplicated Urinary Tract
Infections in Women. Antimicrob Agents Ch, 38(5): 1176-1177.
226
Reddy KH and MM Reddy, 2012. In-Vitro Formulation and Evaluation of Cefixime Liposome
Formulation. Int J Pharm Bio Sci, 2(2): 198-207.
Reddy TM, M Sreedhar and SJ Reddy, 2003. Voltammetric Behavior of Cefixime and
Cefpodoxime Proxetil and Determination in Pharmaceutical Formulations and Urine. J
Pharmceut Biomed, 31(4): 811-818.
Reed MD, WM Gooch, SD Minton, J Tanaka-Kido, JI Santos, TS Yamashita and JL Blumer,
1991. Ceftizoxime Disposition in Neonates and Infants during the First Six Months of
Life. DICP, 25: 344–7.
Regazzi MB, G Chirico, D Cristiani, G Rondini and R Rondanelli, 1983. Cefoxitin in Newborn
Infants. Eur J Clin Pharmacol, 25(4): 507-509.
Remington, 1975. Pharmaceutical Scioences: Ed. 15, Mack Publishing Co., Easton,
pennosylvania.
Renihold JG, 1945. Am. J. M. Sc., 210: 141-147.
Renlund M and O Pettay, 1977. Pharmacokinetics and Clinical Efficacy of Cefuroxime in the
Newborn Period. Proc R Soc Med. 70(9): 179–182.
Rinn JL, JS Rosowsky and IJ Laurenzi, 2004. Major Molecular Differences between Mammalian
Sexes are involved in Drug Metabolism and Renal Function. Dev Cell, 6(6): 791-800.
Risser WL, JS Barone, PA Clark and DL Simpkins, 1987 . Non-Comparative Open Label
Multicenter Trial of Cefixime for Treatment of Bacterial Pharyngitis, Cystitis and
Pneumonia in Pediatric Patients. Pediatr Infect Dis J, 6: 1 002-1006.
Robert COJ, P Tessier, CH Nightingale, PG Ambrose, R Quintiliani and DP Nicolau, 2001.
Pharmacodynamics of Ceftriaxone and Cefixime against Community-Acquired
Respiratory Tract Pathogens. Int J Antimicrob Ag, 17(6): 483–489
Rolls BJ, RJ Wood, ET Rolls, H Lind, W Lind and JGG Ladeingham, 1980. Thirst Following
Water Deprivation in Humans. J Am J Physiol, 239(5): 476-482.
Rowe B, L R Ward and EJ Threlfall, 1 9 9 0 . Spread of Multi-resistant S. typhi. Lancet, 336:
1065-1069.
Rule R, M Rubio and MC Perelli, 1991. Pharmacokinetics of Ceftazidime in Sheep and its
Penetration into Tissue and Peritoneal Fluids. Res Vet Sci, 51: 233-238.
227
Sabati AMA, AS Abdalwali and AAH Mahmoud, 2014. Study of Two Brands of Cefuroxime
500 mg Tablets (Bioxime® and Zinnat®) in Adults Healthy Volunteers. J Chem Pharm
Res, 6(6): 2823-2829.
Saikrishna K, G Akula, VP Pandey, K Sreedevi, S Bhupathi and SR Banda, 2010. Validation of
Reversed-Phase HPLC Method for the Estimation of Cefixime in Cefixime Oral
Suspension. Int J Pharm and Tech, 2(2): 385-395.
Saito A, 1985. Pharmacokinetic Studies on Cefixime. Chemotherapy, 33(6): 190-203.
Samadi AR, 1982. Chloramphenicol-resistant Salmonella typhi N I Phage Type A Isolated from
Patients in Bangladesh. Laancet, 1: l125-1131.
Schaad HJ, GB Petty, DM Grasela, B Christofalo, R Raymond and M Stewart, 1 9 9 7 . Pharmacokinetics
and Safety of a Single Dose of Stavudine in Patients with Severe Hepatic Impairment.
Antimicrob Agents Ch, 41: 2793-2796.
Schlattjan JH, F Biggemann and J Greven, 2005. Gender Differences in Renal Tubular
Taurocholate Transport. N S Arch Pharmacol, 371(6): 449-456.
Schwartz JB, 2003. The influence of sex on pharmacokinetics. Clin Pharmacokinet, 42(2): 107-
121.
Schwartz JB, 2007. The Current State of Knowledge on Age, Sex, and their Interactions on
Clinical Pharmacology. Clinical Pharmacology and Therapeutics, 82(1): 87-96.
Schwartz JB, 2004. The influence of sex on pharmacokinetics [published correction appears
in Clin Pharmacokinet. 2004; 43(11): 732]. Clin Pharmacokinet. 2003; 42(2): 107–121.
Shah J, MR Jan, S Shah and Inayatullah, 2011. Spectrofluorimetric Method for Determination
and Validation of Cefixime in Pharmaceutical Preparations through Derivatization with
2-Cyanoacetamide. J Fluoresc, 21(2): 579-585.
Shah PB and K Pundarikakshudu, 2006. Spectrophotometric, Difference Spectroscopic and
High-Performance Liquid Chromatographic Methods for the Determination of Cefixime
in Pharmaceutical Formulations. J AOAC Int, 89(4): 987-994.
Shargel L and ABC Yu, 1999. Applied Biopharmaceutics and Pharmacokinetics. 4th Edition
McGraw-Hill/Appleton & Lange, Stamford, CT, USA.
Sharma SK and AK Srivastava, 2006. Subcutaneous Pharmacokinetics and Dosage Regimen of
Cefotaxime in Buffalo Calves (Bubalus bubalis). J Vet Sci, 7(2): 119-122.
228
Sharma SK and KS Anil, 2003. Cefotaxime Pharmacokinetics in Male Buffalo Calves Following
Multiple Dosing. Vet Arhiv, 73(4): 191-197.
Sharma SK and SAU Haq, 2012. The Pharmacokinetics of Ceftazidime in E. Coli
Lipopolysaccharide Induced Febrile Buffalo Calves. Vet Arhiv, 82 (6): 555-565.
Sharma SK, KS Anil and DD Milind, 2006. Effect of E. coli Lipopolysaccharides-Induced Fever
on the Disposition Pattern of Cefotaxime in Buffalo Calves. Vet Arhiv, 76 (6): 537-545.
Shoaib MH, D Shaikh, RI Yousuf, BS Naqvi and K Hashmi, 2008. Pharmacokinetic Study of
Cephradine in Pakistani Healthy Male Volunteers. Pak J Pharm Sci, 21(4): 400-406.
Shuil HJ, GR Wilkison, R Johnson and S Schenker, 1 9 76 . Normal Disposition of Oxazepam
in Acute Viral Hepatitis and Cirrhosis. Ann lntern Med, 84: 420-425.
Shu-ying D, T Xu-hui, LI Jian-chun, Z Zhi-tao, ZHU Xiao-guang and J Zhi-wen, 2009.
Bioequivalence of cefixime orally disintegrating tablets in healthy volunteers. Chin J
Hosp Pharm, 20: 1739-1742.
Shyu WC, VR Shah, DA Campbell, J Venitz, V Jaganathan, KA Pitrman, RB Wilber and RH
Barbhaiya, 1992. Excretion of Cefprozil into Human Breast Milk. Antimicrob Agents Ch,
36(5): 938-941.
SilaOn A, U Pavaro and W Nuchpramoo, 1991. Serum and Urinary Uric Acid Levels in Healthy
Subjects and in Patients with Urolithiasis. J Med Assoc Thai. 74(8): 352-7.
Silber DM, W Bohaychuk and M Stout, 1988. Pharmacokinetics of Cefixime in Young and Elderly
Volunteer. Chemotherapy, 1: 18-20.
Silverio J and JW Poole, 1973. Serum Concentration of Ampicillin in Newborn Infants after Oral
Administration. Pediatr, 51: 578-580.
Singlas E, D Lebrec, C Gaadin, G Montay, G Roche and AM Tabburet, 1989. Effect of
Hepatic Failure upon the Pharmacokinetics of Cefixime. Presse Med, 18: 1587-1588.
Soback S and G Ziv, 1988. Pharmacokinetics and Bioavailability of Ceftriaxone Administered
Intravenously and Intramuscularly to Calves. Am J Vet Res, 49(4): 535-538.
Soback S, 1988. Pharmacokinetics of Single Doses of Cefoxitin Given by the Intravenous and
Intramuscular Routes to Unweaned Calves. J Vet Pharmacol Ther, 11(2): 155–162.
Soback S, A Bor and G Ziv, 1987. Clinical Pharmacology of Cefazolin in Calves. Zentralbl
Veterinarmed A, 34(1): 25–32.
229
Soback S, G Ziv, B Kurtz B and Paz R, 1987. Clinical Pharmacokinetics of Five Oral
Cephalosporins in Calves. Res Vet Sci, 43(2): 166–172.
Somekh E, L Heifetz, M Dan, F Poch, H Hafeli and A Tanai, 1996. Penetration and Bactericidal
Activity of Cefixime in Synovial Fluid. Antimicrob Agents Ch, 40(5): 1198-1200.
Sommers DK, L Walters, MV Wyk, SM Harding, AM Paton and J Ayrton, 1983.
Pharmacokinetics of Ceftazidime in Male and Female Volunteers. Antimicrob Agents
Ch, 23(6): 892-896.
Sommers DK, M VanWyk, J Moncrieff and HS Schoe-man, 1984. Influence of Food and
Reduced Gastric Acidity on the Bioavailability of Cefuroxime Axetil. Brit J Clin
Pharmacol, 18: 535-539.
Song CS, NA Glib and SM Wolff, 1972. The Influence of Pyrogen Induced Fever on
Salicylamide Metabolism in Man. J Clin Invest, 51: 2959-2966.
Soons PA, C Grib, DD Brewer and W Arid-Kimh, 1 9 9 2 . Effects of Febrile Infectious Disease on the
Oral Pharmacokinetics and Effects of Nitrendipine Enantiomers and of Bisoprolol. Clin
Pharmacokinet, 23: 238-248.
Staib AH, D Schuppan, R Lissner, W Zilly, G Von-Bomhard and E Richter, 1980. Pharmacokinetics
and Metabolism of Theophylline in Patients with Liver Disease. Int J Clin Pharmacol Ther
Toxicol, 18: 500-502.
Stamper MA, GP Mark, GA Lewbart, SB May, DD Plummer and MK Stoskopf, 1999.
Pharmacokinetics of Ceftazidime in Loggerhead Sea Turtles (Caretta Caretta) After
Single Intravenous and Intramuscular Injections. J Zoo Wildlife Med, 30(1): 32-35.
Standiford HC, GL Drusano, WB MacNamee, B Tatem, PA Ryan and SC Schimpff, 1982.
Comparative Pharmacokinetics of Moxalactam, Cefoperazone, and Cefotaxime in
Normal Volunteers. Rev Infect Dis, 4: 5585-5594.
Stone JW, G Linong, JM Andrews and R Wise, 1988. Cefixime, In-Vitro Activity,
Pharmacokinetics and Tissue Penetration. J Antimicrob Chemoth, 23(2): 221-228.
Succari M, MJ Foglietti and F Percheron, 1990. Microheterogeneity Of Alpha 1-Acid
Glycoprotein: Variation During The Menstrual Cycle In Healthy Women, And Profile In
Women Receiving Estrogen-Progestogen Treatment. Clin Chim Acta, 187(3): 235- 241.
230
Sudhakar M, RJ Venkateshwara, GS Devika and PR Ramesh, 2010. A Validated RP-HPLC
Method for Simultaneous Estimation of Cefixime Trihydrate and Ornidazole in Tablet
Dosage Forms. Int J Chem and Pharm Sci, 1(2): 34-39.
Sugimoto M, I Uchida, T Mashimo, S Yamazaki, K Hatano, F Ikeda, Y Mochizuki, T Terai, and
N Matsuoka, 2003. Evidence for the Involvement of GABAA Receptor Blockade in
Convulsions Induced By Cephalosporins. Neuropharmacology, 45: 304-314.
Sullivan JT, JT Lettieri, P Liu and AH Heller, 2001. The Influence of Age and Gender on the
Pharmacokinetics of Moxifloxacin. Clin Pharmacokinet, 1: 11-18.
Suskind RM, 1975. Gastrointestinal Changes in the Malnourished Children. Pediatr Clin N Am, 22:
873-883.
Swati, S Tiwari, UD Patel, SK Bhavsar and AM Thake, 2010. Pharmacokinetics and Bioavailability of
Ceftriaxone in Patanwadi Sheep. Vet Scan, 5(2): Article 66.
Syed GB, D B Sharma and RK Rama, 1 9 8 6 . Pharmacokinetics of Phenobarbitone in Protein Energy
Malnutrition. Dev Pharmacol Ther, 9: 317-322.
Szefler SJ, RJ Wynn and DF Clarke, 1 9 8 0 . Relationship of Gentamicin Serum Concentration to
Gestational Age in Pre-Term and Term Neonates. J Pediatr, 97: 312-315.
Takase Z, T Miyoshi, M Fujiwara, N Nakayama and Y Komoto, 1985. A Fundamental and Clinical
Study of Cefixime in Obstetrics and Gynecology. Chemotherapy, 33(6): 785-795.
Tanaka E, 2002. Clinically Significant Pharmacokinetic Drug Interactions between Antiepileptic
Drugs. J Clin Pharm Ther, 24(2): 87–92.
Tanimura H, N Kobayashi, T Saito and WF Huang, 1985. Chemotherapy of Biliary Tract Infections:
Concentration of Cefixime in Bile and Gallbladder Tissue and Clinical Evaluation on Biliary
Tract Infections. Chemotherapy, 33(6): 499-517.
Tantituvanont A, W Yimprasert, P Werawatganone and D Nilubol, 2009. Pharmacokinetics of
Ceftiofur Hydrochloride in Pigs Infected with Porcine Reproductive and Respiratory
Syndrome Virus. J Antimicrob Chemoth, 63: 369-373.
Tatsutu M, H Ishikawa, H Jishi, S Okuda and Y Yokota., 1990. Reduction of Gastric Ulcer
Recurrence after Suppression of Helicobacter Pylori by Cefixime. Gut, 31: 973-976.
Taylor DN, RA Pollard and PA Blak, 1 9 8 3 . Typhoid in the United States and the Risk to the
International Traveler. J Infect Dis, 148: 599-602.
231
Thiessen JJ, EM Sellers, P Denbeigh and L Dolman, 1976. Plasma Protein Binding of Diazepam and
Tolbutamide in Chronic Alcoholics. J Clin Pharmacol, 16: 345-351.
Thurman RG and FC Kauffman, 1 9 8 0 . Factors Regulating Drug Metabolism in Intact Hepatocytes.
Pharmacol Rev, 31: 229-251.
Thyrum PT, C Yeh, B Birmingham and K Lasseter, 1997. Pharmacokinetics of Meropenem in
Patients with Liver Disease. Clin Infect Dis, 24: 5184-5190.
Timmer CJ, JM Sitsen and LP Delbressine, 2000. Clinical Pharmacokinetics of Mirtazapine. Clin
Pharmacokinet, 38(6): 461-474.
Tiwari S, Swati, SK Bhavsar, UD Patel and AM Thaker, 2009. Disposition of Ceftriaxone in Goats (Capra
hircus). Vet Scan, 4(2): Article 41.
Tomasz A, 1986. From Penicillin-Binding Proteins to the Lysis and Death of Bacteria. Rev Infect Dis,
1: 434-467.
Toth ABS, HY Abdallah, R Venkataramanan, L Teperman, G Halsf, M Rabinovitch, GJ
Burckart and TE Starzl, 1991. Pharmacokinetics of Ceftriaxone in Liver-transplant
Recipients. J clin pharmacol. 31(8): 722–728.
Tranvouez JL, E Lerebours, P Chretien, H Fouin-Fortunet and R Colin, 1985. Hepatic Antipyrine
Metabolism in Malnourished Patients: Influence of Therapy of Malnutrition and Course after
Nutritional Rehabilitation. Am J Clin Nutr, 41: 1257-1264.
Trenholme GM, RL Williams and KH Ricckmann, 1976. Quinine Disposition during Malaria and During
Induced Fever. Clin Pharmacol Ther, 19: 459-467.
Tsuji A, H Hirooka, T Terasaki, I Tamai and E Nakashima, 1987b. Saturable Uptake of
Cefixime, a New Oral Cephalosporin without an Alpha-Amino Group, By the Rat
Intestine. J Pharm Pharmacol, 4: 272-277.
Tsuji A, T Terasakd, I Tamai and H Hirooka, 1987a. H+ Gradient-Dependent and Carrier-
Mediated Transport of Cefixime, Across Brush-Border Membrane Vesicles from Rat
Intestine. J Pharmacol Exp Ther, 241: 594-601.
United States Pharmacopoiea, USP 30, NF 25, (2007).
Vallee F and L Marc, 1991. Comparative Study of Pharmacokinetics and Serum Bactericidal
Activity of Ceftizoxime and Cefotaxime. Antimicrob Agents Ch, 35(10): 2057-2064.
232
Vandenanker JN, RC Schoemaker, BJ VanderHeijden, HM Broerse, HJ Neijens and RDE Groot,
1995. Once-Daily versus Twice-Daily Administration of Ceftazidime in the Preterm
Infant. Antimicrob Agents Chemoth, 2048–2050.
Vesell ES, JG Page and GT Passanati, 1 9 7 1 . Genetic and Environmental Factors Affecting
Ethanol Metabolism in Man. Clin Pharmacol Ther, 12: 192-194.
Vogel F and AG Motulsky, 1986. Human Genetics: Problem and Approaches. Springer New
York.
Wagh S, H Aga, M Avachat and H Sen, 2005. Novel Pharmaceutical Formulation of Cefixime
for Enhanced Bioavailability. http://www.google.co.in/patents/WO2005107703A1?cl=en
Wagner JC, 1975. Pharmcokinetics and Bioavailability. Triangle. 1975, 14: 101-104.
Wagner JG and JJ Northham, 1967. Estimation of Volume of Distribution and Half of a
Compound after Rapid Interavenous Injection. J Pharm Sci, 56: 529-531.
Wagner JG, PK Wilkinson, AJ Sildman and RG STOLL, 1973. Failure of USP Tablet
Disintegration Test to Predict Performance in Man. J Pharm Sci, 62: 859-860.
Walker MC, WM Lam and KB Manasco, 2012. Continuous and Extended Infusions of Β-Lactam
Antibiotics in the Pediatric Population. Ann Pharmacother, 46: 1537-1546.
Walker O, AH Dawodu, LA Salako, G Alvan and AO Johnson, 1 9 8 7 . Single Dose Disposition of
Chloroquine in Kwashiorkor and Normal Children Evidence for Decreased Absorption in
Kwashiorkor. Brit J Clin Pharmacol, 23: 467-472.
Walle T, RP Byington and CD Furberg, 1985. Biologic Determinants of Propranolol Disposition:
Results from 1308 Patients in the Beta-Blocker Heart Attack Trial. Int J Clin Pharm Th,
38(5): 509-518.
Walle UK, TC Fagan and MJ Topmiller, 1994. The Influence of Gender and Sex Steroid
Hormones on the Plasma Binding of Propranolol Enantiomers. Brit J Clin Pharmaco,
37(1): 21-25.
Wankhede AR, PY Mali, V Karne, AR Khale and CS Magdum, 2010. Development and
Validation of RP-HPLC Method for Simultaneous Estimation of Cefixime and
Cloxacillin in Tablet Dosage Form. IJPBA, 1(2): 317-320.
233
Wenzel U, S Kuntz, S Diestel and H Daniel, 2002. Pepti-Mediated Cefixime Uptake Into Human
Intestinal Epithelial Cells Is Increased By Ca Channel Blockers. Antimicrob Agents Ch,
1375-1380.
Westphal JF, F Jehl, M Schloegel, H Monteil and JM Brogard, 1993. Biliary Excretion of
Cefixime: Assessment in Patients Provided With T-Tube Drainage. Antimicrob Agents
Ch, 37(7): 1488-1491.
Westphal JF, JM Brogard, F Jehl, M Schloegel, JF Blickle and H Monteil, 1992. Evaluation of
Cefixime Biliary Disposition in the Isolated Perfused Rabbit Liver Model and In
Humans. . Drugs Exp Clin Res, 18 (8): 329-336.
Whitley H and W Lindsey, 2009. Sex-based Differences in Drug Activity. Am Fam
Physician, 80(11): 1254-1258.
Whitley HP, 2009. Sex-Based Differences in Drug Activity. Am Fam Physician, 80(11): 1254-
1258.
Wilson RC, DD Goetsch and TL Huber, 1984. Influence of Endotoxin-Induced Fever on the
Pharmacokinetics of Gentamicin in Ewes. Am J Vet Res, 45: 2495-2497.
Wood AJ, DM Komhascr and GR WiIkinson, 1 9 7 8 . The Influence of Cirrhosis on Steady-
State Blood Concentration of Unbound Propranolol after Oral Administration. Clin
Phamacokinet. 1: 478-487.
Xue FS, SY Tong, X Liao, JH Liu, G An and LK Luo, 1997. Dose–Response and Time Course of
Effect of Rocuronium in Male and Female Anesthetized Patients. Anesth Analg, 85: 667–
671.
Yan Z., HEJ Rong and WA Dong, 2003. Bioequivalency and Pharmacokinetics of Oral
Dispersion Tablets of Cefixime in Healthy Volunteers. Chin J Hosp Pharm, 2003-7.
Yaoguo S, Q Zhang, J Yu, L Wang and Y Zhang, 1994. Pharmacokinetics of Cefixime in Healthy
Volunteers. J Antibiot, 4(1): 45-52.
Yi Z, S Zhongshi, L Qingdi and L Mantang, 1995. Pharmacokinetics of Cefixime in Patients
with Respiratory Tract Infections. Chin Pharm J, 1995-10.
Ying Z, X Zhao, P Sun, W LiuYu, D Zhao and Z Sun, 2003. Study on Bioequivalence of
Cefixime Capsule in Healthy Volunteers. J Clin Pharmacol, 12(3): 97-102.
234
Yu-fei F, Q Yin, K Gao, A Shi, K Li and C Sun, 2004. Pharmacokinetics and Bioequivalence of
Cefixime in Healthy Volunteers. Chinese Journal of New Drugs, S1.
Yukawa E, T Honda, S Ohdo, S Higuchi and T Aoyama, 1997. Population‐Based Investigation
of Relative Clearance of Digoxin in Japanese Patients by Multiple Trough Screen
Analysis: An Update. J Clin Pharmacol, 37(2): 92-100.
Zakeri-Milani P, H Valizadeh and Z Islambulchilar, 2008. Comparative Bioavailability Study of
Two Cefixime Formulations Administered Orally in Healthy Male Volunteers. Biopharm
Drug Dispos, 58(2): 97-100.
Zendelovska D, T Stafilov and P Milosevski, 2003. High Performance Liquid Chromatographic
Method for Determination of Cefixime and Cefotaxime in Human Plasma. Bull Chem
Technol Macedonia, 22(1): 39-45.
Zhao L, Q Li, X Li, R Yin, X Chen, L Geng and K Bi, 2012. Bioequivalence and Population
Pharmacokineticmodeling of Two Forms of Antibiotic, Cefuroxime Lysine and
Cefuroxime Sodium, After Intravenous Infusion in Beagle Dogs. J Biomed Biotechnol,
2012: 1-9.
Zhao L, R Yin, BB Wei, Q Li, ZY Jiang, XH Chen and BS Kai 2012b. Comparative
Pharmacokinetics of Cefuroxime Lysine after Single Intravenous, Intraperitoneal, and
Intramuscular Administration to Rats. Acta Pharmacol Sin, 33: 1348–1352.
Zhou HH, YP Chan, K Arnold and M Sun, 1985. Single-Dose Pharmacokinetics of Ceftriaxone
in Healthy Chinese Adults. Antimicrob Agents Ch, 27(2): 192-196.
Ziv G, 1975. Pharmacokinetic Concepts for Systemic and Intramammary Antibiotics Treatment
in Lactating and Dairy Cows. J Dairy Sci, 58: 938-946.
Ziv G, E Lavy, A Glickman and M Winkler, 1995. Clinical Pharmacology of Cefixime in
Unweaned Calves. J Vet Pharmacol Ther, 18(2): 94-100.
235
APPENDICES
Appendix 1: Laboratory investigation of 10 healthy female subjects involved in
pharmacokinetic and bioequivalence study of cefixime.
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
Appendix 2: Laboratory investigation of 10 healthy male subjects involved in pharmacokinetic
and bioequivalence study of cefixime.
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274