Upload
fiona-oyatsi
View
227
Download
0
Embed Size (px)
Citation preview
8/10/2019 [3]-Drug Metabolism-Lect.ppt
1/35
8/10/2019 [3]-Drug Metabolism-Lect.ppt
2/35
Introduction
Drug metabolism (biotransformation or detoxication)isthe biochemical changes of the drugs and other foreignsubstances in the body.
This is leading to the formation of different metabolites with
different effects.
Some of the compounds are excreted partially unchanged andsome are known to be converted to products, which may be moreactive or more toxic than the parent compounds.
The liver is the major site of drug metabolism, but specific
drugs may undergo biotransformation in other tissues.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
3/35
Importance
Drug metabolism is needed to convert non-polar
lipophilic compounds (lipid soluble) which the body
cannot excrete into more polar hydrophilic compounds
(water soluble) which the body can excrete them in
short period of time.
Because if the lipid soluble non-polar compounds are
not metabolized to the polar water soluble compounds,
they will remain in the blood and tissues and maintain
their pharmacological effects for an indefinite time.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
4/35
8/10/2019 [3]-Drug Metabolism-Lect.ppt
5/35
1-Inactive metabolites: Some metabolites are inactive,i.e. their pharmacological active parent compound become
inactive.
Examples:
i) Hydrolysis of procaine top-aminobenzoic acid anddiethylethanolamine results in loss of anesthetic activity ofprocaine.
ii) Oxidation of 6-mercaptopurine to 6-mercapturic acid resultsin loss of anticancer activity of this compound.
6-Mercaptopurine 6-Mercapturic acid (inactive)
NH2
O
N
O
NH
N
O
CH3CH3
H2N-C6H5-COOH + Et2N-CH2CH2OHInactive metabolites
8/10/2019 [3]-Drug Metabolism-Lect.ppt
6/35
2-Metabolites retain similar activity:Some metabolite retain the pharmacological activity of their parent
compounds to a greater or lesser degree.
Examples:i) Codeine is demethylated to the more active analgesic morphine
ii) Phenacetin is metabolized to more active paracetamol
iii) Imipramine is demethylated to the equiactive antidepressant
desipramine.
3-Metabolites with different activity:Some metabolites develop activity different from that of their
parent drugs.
Examples:i) Iproniazid (antidepressant) is dealkylated to isoniazid
(antitubercular)
ii) Retinoic acid (vitamin A) is isomerized to isoretinoic acid (anti-acne agent).
8/10/2019 [3]-Drug Metabolism-Lect.ppt
7/35
4-Bioactivated metabolites (activation ofinactive drugs):
Some inactive compounds are converted to active drugs within
the body.These compounds are called prodrugs.
Prodrugs may have advantages over the active form (activemetabolite) as more stable, having better bioavailability or
less side effects and toxicity.Examples:i) Levodopa (antiparkinson disease) is decarboxylated in the
neuron to active dopamine
ii) The prodrug sulindac a new non steroidal antiinflammatorydrug (sulfoxide) is reduced to the active sulfide
iii) Benorylate to aspirin and paracetamol
iv) The prodrug enalapril is hydrolysed to enalaprilat (potent
antihypertension).
8/10/2019 [3]-Drug Metabolism-Lect.ppt
8/35
Biotransformation Pathways
Drug metabolism reactions have been divided into two classes:
i)
Phase I reaction (functionalization ) andii) Phase II reaction (conjugation)
Phase I reaction: Polar functional groups are either
introduced into the molecule or modified by oxidation,
reduction or hydrolysis.
Or convert lipophilic molecules into more polar molecules by
introducing or exposing polar functional groups.
E.g. aromatic and aliphatic hydroxylation or reduction ofketones and aldehydes to alcohols.
Phase I reactions may increase or decrease or leave
unaltered the pharmacological activity of the drugs
8/10/2019 [3]-Drug Metabolism-Lect.ppt
9/35
1-Oxidation:
Addition of oxygen or removal of hydrogen.
Normally the first and most common step involved in the drugmetabolism
Majority of oxidation occurs in the liver and it is possible to occur in
intestinal mucosa, lungsand kidney.
Most important enzyme involved in this type of oxidation iscytochrome P450
Increased polarityof the oxidized products (metabolites) increases
their water solubility and reduces their tubular reabsorption,
leading to their excretion in urine.These metabolites are more polarthan their parent compounds and
might undergo further metabolism by phase II pathways
8/10/2019 [3]-Drug Metabolism-Lect.ppt
10/35
2- Reduction:
is the converse of oxidation (i.e. removal of oxygen or
addition of hydrogen).
E.g. reduction of aldehydes and ketones, reduction of nitro
and azo compounds.
It is less common than oxidation, but the aim is same tocreate polar functional groups that can be eliminated in
the urine.
Cytochrome P450 system is involved in some reaction.
Other reactions are catalyzed by reductasesenzymes
present in different sites within the body.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
11/35
11
3-Hydrolysis:
It is the reaction between a compound and water.
The addition of water across a bond also gives more polarmetabolites.
Different enzymes catalyze the hydrolysis of drugs:
Esterase enzymesAmidase enzymes
8/10/2019 [3]-Drug Metabolism-Lect.ppt
12/35
1- Esterase enzymes:
Usually present in plasma and various tissues, are nonspecific and
catalyze de-esterification. Hydrolysis of nonpolar esters into two
polar and more water soluble compounds (i.e. acid and alcohol).
O
C ORCH3 H2O
O
C OHCH3 ROH+ +
Ester of acetic acid Acetic acid Alcoh
Esterases are responsible for converting many prodrugs intotheir active forms.A classical example of ester hydrolysis is the metabolic
conversion of aspirin (acetylsalicylic acid) to salicylic acid andacetic acid. COOH
OCOCH3
COOH
OH
H2O CH3COOH+
Aspirin Salicylic acidAcetic acid
8/10/2019 [3]-Drug Metabolism-Lect.ppt
13/35
2-Amidase enzymes:
It is the hydrolysis of amides into amine and acid and this iscalled Deamination.Deamination occurs primarily in the liver.
O
C RNH2 H2O
O
C OHR NH3+ +
Amide Water Acid Ammo
Amide drugs are more resistant to hydrolysis (or they are nothydrolyzed until they reach the liver) than ester drugs which
they are susceptible to plasma esterase.
The duration of actions of ester drugs are less than the
amide analogues.Example:Procaine (ester type) injection or topical is usually shorteracting than its amide analogue procainamide administeredsimilarily.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
14/35
Phase II conjugation ReactionsWhen phase I reactions are not producing sufficiently hydrophilic(water soluble) or inactive metabolites to be eliminated from thebody, the drugs or metabolites formed from phase I reactionundergoes phas II reactions.
Generally phase I reactions provide a functional groups or handle inthe molecule that can undergo phase II reactions. Thus, phase IIreactions are those in which the functional groups of the original
drug (or metabolite formed in a phase I reaction) are masked by aconjugation reaction.
Phase II conjugation reactions are capable of converting thesemetabolites to more polar and water soluble products.
Many conjugative enzymes accomplish this objective by attaching small,polar, and ionizable endogenous moleculessuch as glucuronic acid ,sulfate, glycine, glutamine and glutathioneto the phase I metaboliteor parent drug. The resulting conjugated products are very polar (watersoluble), resulting in rapid drug elimination from the body.
Ph II C j ti R ti
8/10/2019 [3]-Drug Metabolism-Lect.ppt
15/35
Phase II Conjugation Reactions
These reactions require both a high-energy molecule and an enzyme.
The high-energy moleculeconsists of a coenzyme which is bound to theendogenous substrate and the parent drug or the drugs metaboliteresulted from phase I reaction.
The enzymes that catalyzed conjugation reactions are called
transferases, found mainly in the liver and to a lesser extent in theintestines and other tissues.
Most conjugates are biologically inactive and nontoxic because they arehighly polar and unable to cross cell membrane.
Exceptions to this are acetylated and methylatedconjugatesbecause these phase II reactions(methylation and acetylation) doesnot generally increase water solubility but serve mainly to terminate orreduce pharmacological activity (they are usually pharmacologicallyinactive).
8/10/2019 [3]-Drug Metabolism-Lect.ppt
16/35
Conjugating molecules:
o 1- Glucuronic acid conjugation:
o It forms O-glucuronideswith phenols Ar-OH,alcohols R-OH, hydroxylamines H2N-OH,andcarboxylic acid RCOOH.
o It can form N-glucuronideswith sulfonamides,
amines, amides, and S-glucuronideswith thiols.o 2-Sulfate conjugation:o It is less common.o It is restricted to phenols, alcohols, arylamines, and
N-hydroxyl compounds.o But primary alcohols and aromatic hydroxylamines
can form unstable sulfate conjugates which can betoxic.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
17/35
Conjugating molecules:
3-Amino acid conjugation: By the formation of peptide link. With glycine or
glutamine.
4- Glutathione conjugation:
It reacts with epoxides, alkylhalides, sulfonates,disulfides, radical species.
These conjugates are converted to mercapturicacid and mostly are excreted in bile. It isimportant in detoxifying potentially dangerousenvironmental toxins.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
18/35
8/10/2019 [3]-Drug Metabolism-Lect.ppt
19/35
Th i j ti th
8/10/2019 [3]-Drug Metabolism-Lect.ppt
20/35
20
There are six conjugation pathways:
3)-Amino acid conjugation:
CS
CoA
O
R+
H2N CO2H
YH
N CO2H
YH
CR
O
H
Y = H or CH2CH2CO2HAcyl coenzyme A
N-acyltransferasecatalyses the conjugation reaction
4)-Glutathione conjugation
C
S
CoA
O
R
+
H2N CO2H
YH
N CO2H
YH
C
R
O
H
Y = H or CH2CH2CO2HAcyl coenzyme A
Glutathione S-transferase catalyses this conjugation
reaction
8/10/2019 [3]-Drug Metabolism-Lect.ppt
21/35
5)-Methylation
6)-Acetylation
N-acyltransferasecatalyses the conjugation reaction
Methyltransferase catalyses this conjugation reaction
OAdenine
S+
NH2
HO2C
CH3
HOH2O3PO
R X+ R X CH3
SAM
X = OH, NH2, SH
Aceyl CoAY =NH2, NHNH2, SO2NH2, CONH2
RXCR
O
+CS
CoA
O
H3CR X
8/10/2019 [3]-Drug Metabolism-Lect.ppt
22/35
Extrahepatic metabolism
Refers to drug biotransformation that takesplace in tissues other than the liver.
The most common sites include the plasma, GImucosa, nasal passages, lungs and kidneys.However, metabolism can occur throughoutthe body.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
23/35
23
Factors influencing Drug
Metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
24/35
F t i fl i D M t b li
8/10/2019 [3]-Drug Metabolism-Lect.ppt
25/35
25
Factors influencing Drug Metabolism 4-Genetic variations:
Isoniazid is known to be acetylated by N-acetyltransferase into inactive metabolite.
The rate of acetylation in asian people is higher or fasterthan that in eurpoean or north american people. Fast
acetylators are more prone to hepatoxicity than slowacetylator.
5-Drug dosing: 1- An increase in drug dosage would increase drug
concentration and may saturate certain metabolicenzymes.
2- when metabolic pathway becomes saturated, an
alternative pathway may be pursued.
F t i fl i D M t b li
8/10/2019 [3]-Drug Metabolism-Lect.ppt
26/35
Factors influencing Drug Metabolism
6-Nutritional status:
1-Low protein diet decreases oxidative reactions orconjugation reactions due to deficiency of certain aminoacids such as glycine.
2-Vitamin deficiency of A,C,E, and B can result in a
decrease of oxidative pathway in case of vitamin Cdeficiency , while vitamin E deficiency decreasesdealkylation and hydroxylation.
3-Ca, Mg, Zn deficiencies decreases drug metabolism
capacity whereas Fe deficiency increases it. 4-Essential fatty acid (esp. Linoleic acid) deficiency
reduce the metabolism of ethyl morphine and hexobarbitalby decreasing certain drug-metabolizing enzymes.
Factors influencing Drug Metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
27/35
Factors influencing Drug Metabolism
7-Age:1- Metabolizing enzymes (sp.glucuronide conjugation)are not
fully developed at birth, so infants and young childrenneed to take smaller dosesthan adults to avoid toxiceffects.
2-In elderly, metabolizing enzyme systems decline.
8-Gender (sex):Metabolic differences between females and males have been
observed for certain compoundsMetabolism of Diazepam, caffiene, and paracetamol is faster
in females than in males while oxidative metabolism oflidocaine, chordiazepoxide are faster in men than in
females
Factors influencing Drug Metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
28/35
Factors influencing Drug Metabolism
9-Drug administration route:
1-Orally administered drugs are absorbed from theGIT and transported to the liver before entering the
systemic circulation. Thus the drug is subjected to
hepatic metabolism (first pass effect) before reaching
the site of action.
2-Sublingually and rectally administered drugs take
longer time to be metabolized than orally taken
drugs.Nitroglycerine is ineffective when taken orallydue to hepatic metabolism.
3-IVadministration avoid first pass effect because the
drug is delivered directly to the blood stream.
Factors influencing Drug Metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
29/35
Factors influencing Drug Metabolism
10-Enzyme induction or inhibition
Several antibiotics are known to inhibit the activity ofcytochrome P450.
Phenobarbitone is known to be cytochrome P450enzyme inducer while cimetidine is cyt. P450
inhibitor.If warfarin is taken with phenobarbitone, it will be
less effective.
While if it is taken with cimetidine, it will be lessmetabolized and thus serious side effects mayappear.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
30/35
30
Strategies to manage drugmetabolism
Strategies to manage drug metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
31/35
Strategies to manage drug metabolism
1)-Pharmaceutical strategies:by using different dosage forms to either avoid or compensate for
rapid metabolism.1-Sublingual tablets (through mucous mermbrane) by delivering
drugs directly to blood and bypassing first-pass effect asnitroglycerine (antiangina drug).
2-Transdermal patches and ointments: provide continuous supply of
drug over extended period of time and are useful for rapidlymetabolizing drugs suchj as prophylactic nitroglycerine.
3- Intramuscular injections provide a continuous supply of drug overextended period of time such as`lipid soluble esters ofestradiol and testosterone. Hydrolysis of these prodrugs
produce a steady supply of rapidly metabolized hormones.4-Enteric coated formulation can protect acid-sensitive drugs as
erythromycin.5-Nasal administration allows for the delivery of peptides such as
aerosols since they need only to penetrate the thin epithelial
layer to reach the abundant capillary beds
8/10/2019 [3]-Drug Metabolism-Lect.ppt
32/35
Strategies to manage drug metabolism
8/10/2019 [3]-Drug Metabolism-Lect.ppt
33/35
33
Strategies to manage drug metabolism
3)-Chemical strategies
These are molecular modifications involvingthe addition, deletion or isostericmodification of functional groups.
Examples are:1-chlorpropamide was designed from
tolbutamide
2-Methyl testosterone was designed fromtestosterone.
P d t t i
8/10/2019 [3]-Drug Metabolism-Lect.ppt
34/35
34
Prodrugs strategies
Prodrugs are used instead of active form ofthe
drug to:
a) Enhance membrane permeability,
b) Reduce drug toxicity
c) Overcome /mask bad taste
d) Overcome acid sensitivity
e) Prolong (short) duration.
8/10/2019 [3]-Drug Metabolism-Lect.ppt
35/35
Advantages of Prodrugs
1-An increase in water solubility by using sodium succinate esters as
chloramphenicol succinate IV injection.2- An increase in lipid solubilitya-Increase duration of action by using lipid soluble estersb-Increase oral absorption as by using esters of the highly polar drugs
or N-methylationC-Increase topical absorption of steroids by masking OH group asesters or acetonides.
3-A decrease in water solubilityto increase palatability as inchloramphenicol palmitate
4-Decrease GI irritation (side effect) as in aspirin
5-Site specificity as in methyl dopa
6- Increased half-life and chemical stability as in cefamandoleacetate a stable prodrug, while the parent cefamandole is unstables lid d s f H t illi is th d (f i illi )