INTRODUCTION TO PHARMACOKINETICS

• Course:

Introduction to Pharmaceutical Sciences (PHPS 512)

• Required reading:

Pandit, Chapters 9, 11,12,13,14

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2http://www.biology.iupui.edu/biocourses/biol540/4pipeline2CSS.html

PHARMACOKINETICS

1 ABSORPTION1. ABSORPTION

2. DISTRIBUTION

3. METABOLISM

4. EXCRETION

4. EXCRETION

ALL THESE PROCESSES ARE DETERMINED BY THE ABILITY OF A DRUG TOABILITY OF A DRUG TO CROSS BIOLOGICAL MEMBRANES

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1. ABSORPTION:transfer of a drug

g

from site of administration to the systemic circulation

systemic circulation

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ROUTES OF DRUG ADMINISTRATION

ENTERAL: administration into the systemic circulation via the alimentary (digestive) canalvia the alimentary (digestive) canal

• Tablets, capsules, solutions, suspensions– Oral (PO): by mouth– Sublingual (SL): under the tongueSublingual (SL): under the tongue– Rectal (PR): by suppositories

PARENTERALPARENTERAL

TOPICAL

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ROUTES OF DRUG ADMINISTRATIONENTERALENTERALPARENTERAL: administration into the systemic

circulation via routes other than the alimentary canalS l ti l i i l• Solutions, emulsions, suspensions, aerosols, gases– Intravenous (IV): into venous circulation– Intramuscular (IM): into the muscle– Subcutaneous (SC): under the skin, into the ( ) ,

hypodermis– Inhalational: via the lungs– Intrathecal (IT): into spinal subarachnoid space– Epidural: into epidural space outside of duraEpidural: into epidural space outside of dura

mater– Intrasynovial (Intra-articular): into the joint– Intraosseus: into the bone

Intraperitoneal (IP): into the abdominal– Intraperitoneal (IP): into the abdominal (peritoneal) cavity

– Intra-arterial (IA): into arterial circulationTOPICAL

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ROUTES OF DRUG ADMINISTRATION

ENTERAL

PARENTERALPARENTERAL

TOPICAL: administration by direct application onto the ki i t d bskin or associated membranes

• Powders, creams, ointments, gels, sprays, patches– Transdermal: across the skin

Transmucosal: across the mucous membranes– Transmucosal: across the mucous membranes– Ophthalmic: onto membranes of the eye– Vaginal: onto the membranes of vagina– Intrauterine: onto membranes of the uterus liningIntrauterine: onto membranes of the uterus lining

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• Bioavailability is a fraction of unchanged drugDRUG ABSORPTION

Bioavailability is a fraction of unchanged drug reaching the systemic circulation following administrationBioavailability depends• Bioavailability depends– Route of administration– Drug properties (lipophilicity, pKA, formulation)g p p ( p p y p A )– Physiological variables (pH, blood flow, enzymes)

• Effects of route of administration on absorption and bioavailability:bioavailability:– IV = 100% Bioavailability– IM, SC, Inhaled = High Bioavailability but < 100%

O l l d i i bi il bili d l– Oral = low and inconsistent bioavailability and slower absorption• First pass effect

R i li id l bilit

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• Requires lipid solubility• Bioavailability varies with GI motility, presence of food• GI tract = low pH, lots of enzymes

FIRST PASS METABOLISM

• Oral drug administration only Liver - Primary site of drug metabolism in the

• Is avoided with parenteral and non-oral drug

drug metabolism in the body

administration routes

• Extraction ratio (ER) –Extraction ratio (ER)fraction of drug removed by first pass effect

• Could be 90% or more of orally administered dose

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FIRST-PASS METABOLISM

Alternative routes of administration and first-pass metabolism

• Sublingual route (avoids first-pass effect)• Transdermal route (avoids first-pass effect)• Rectal route (decreases first-pass effect by approximately• Rectal route (decreases first-pass effect by approximately

40 to 60%)

Alternative routesAlternative routes• Increase bioavailability of drugs with high extraction ratio

and • Do not significantly affect the bioavailability of drugs with

low hepatic extraction

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DISTRIBUTION

2. DISTRIBUTION:movement of a drug

gfrom the systemic circulation to various sites in the

various sites in the body

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DISTRIBUTION

• Distribution is the movement of drugs throughout the body once they are in the general circulationbody once they are in the general circulation

• It is reversible transfer of drug between vascular and extra vascular space – To sites of actionTo sites of action– To sites of elimination/metabolism– Requires passage through endothelial cells layers

Di t ib ti d d• Distribution depends on– Lipid solubility/size of drug– Drug pKA and blood/tissue pHg p A p– Extent of blood perfusion of tissue– Extent of binding to plasma binding proteins: albumin, 1-acid glycoprotein

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1 acid glycoprotein

DISTRIBUTION

• Distribution into central nervous system –blood-brain barrier– Only very lipophilic drugs will enter the central

nervous system

TIGHT JUNCTIONS

WIDE JUNCTIONS

PERIPHERAL CAPILLARY

CAPILLARY IN THE CENTRAL NERVOUS SYSTEM

JU C O S

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DISTRIBUTION TO CELLULAR SITES OF ACTION: LOCAL ANESTHETICSANESTHETICS

– Local anesthetics will more readily reach their sites of action when they are in their LIPID SOLUBLE (UNCHARGED) FORM

UNCHARGED DRUG

CHARGED DRUG+Voltage Dependent

Sodium ChannelSodium Channel

NEURONAL MEMBRANE

EXTRACELLULAREXTRACELLULAR

INTRACELLULARINTRACELLULAR

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LOCAL ANESTHETICS – WEAK BASES(pKa 7.5 – 9.5)

• EXAMPLE: Lidocaine a weak base with a pK of 7 9• EXAMPLE: Lidocaine a weak base with a pKa of 7.9.

C14H23N2O+ C14H22N2OpH < 7.9 pH > 7.9

Protonated form: charged and lipid

Unprotonated form: uncharged and lipid

insoluble soluble+

EXTRACELLULAREXTRACELLULAR EXTRACELLULAREXTRACELLULAR

SODIUMCHANNEL

15INTRACELLULARINTRACELLULAR INTRACELLULARINTRACELLULAR

CHANNEL

VOLUME OF DISTRIBUTION

V l f di t ib ti i ti f th t f d• Volume of distribution is a ratio of the amount of drug in the body to the concentration of drug in blood or plasma

Vd =Total drug dose

Plasma concentration

• This is an apparent and not physical volume (Vd for digoxin is ~500 L/70 kg)g g)

• This parameter characterizes how well the drug is distributed from the systemic circulation

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DISTRIBUTION OF DIFFERENT TYPES OF DRUGS

• Macromolecular drugs (antibodies, heparin, etc.)Vd = 3 L, or 0.04 L/kg

• Polar small molecule drugs (mannitol) Vd = 12 L, or 0.17 L/kg

• More lipophilic small molecule drugs (diazepam• More lipophilic small molecule drugs (diazepam, lidocaine), distributed in total body water Vd = 40 L, or 0.57 L/kg

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• Very lipophilic small molecule drugs have very high Vd values (larger than the volume of entire body)

Vd AND PROTEIN BINDING• The higher the lipophilicity of• The higher the lipophilicity of

a drug, the greater is the affinity for plasma proteins

• Many drugs are normally• Many drugs are normally greater than 90% bound to plasma proteins

• Drugs extensively bound to• Drugs extensively bound to plasma proteins usually have lower apparent volume of distribution

• When several drugs that bind to the same protein are given together, one drug may g g ydisplace another from the protein binding sites. This causes elevated plasma concentration of the displaced

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concentration of the displaced drug, and increased apparent volume of distribution

DRUG METABOLISM

3. DRUG METABOLISM:biotransformation of

the drug with the goal of promoting its elimination via the

elimination via the kidneys

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BIOTRANSFORMATION REACTIONSBi f i i i il b• Biotransformation reactions occur primarily but not exclusively in the liver (also in some other organs such as skin and lungs and in some cases, e.g., hydrolysis, in the blood)

• Phase I reactions make drug more polar by introducing or unmasking functional groups

• Phase II reactions add endogenous substrate to drug g gto produce a highly polar conjugate. Usually preceded by phase I reactions, but not always

20DRUG POLAR

METABOLITE

PHASE I REACTIONSTypes of phase I reactionsTypes of phase I reactions• Hydrolysis reactions

– Catalyzed by esterases (carboxylesterases, cholinesterases)Cl f t id b d i l l i ti– Cleavage of ester or amide bonds in a molecule via a reaction involving the introduction of water

• Oxidation reactions– Catalyzed by oxidases dehydrogenases oxygenases– Catalyzed by oxidases, dehydrogenases, oxygenases– Involves the loss of electrons from the drug and/or introduction of

molecular oxygen into the drug molecule– The most important Phase I oxidation reaction involves

cytochrome P450 enzymes– Alcohols (ethanol, methanol) are oxidized by a different family of

enzymes that include alcohol and aldehyde dehydrogenasesPurposes of Phase I ReactionsPurposes of Phase I Reactions1. Expose or introduce functional groups on a drug: -OH, -NH2, -SH, -

COOH2. Make a drug more hydrophilic

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a e a d ug o e yd op c3. Provide sites on a drug for Phase II reactions4. In most, but NOT ALL cases, metabolism results in drug inactivation

PHASE I REACTIONSTHE CYTOCHROME P450 SYSTEM

Bi d t d d t l id ti ti• Bind to drugs and catalyze oxidation reactions• Most common Phase I metabolic reactions• Three “families” of cytochrome P450 enzymesThree families of cytochrome P450 enzymes

– CYP1– CYP2– CYP3CYP3

• Altogether there are more than 15 different kinds of drug-metabolizing cytochrome P450 enzymes in the liver

For example: the CYP1 family of cytochrome P450s includes– For example: the CYP1 family of cytochrome P450s includes CYP1A1, CYP1A2, and CYP1B1 enzymes

• Each P450 enzyme can metabolize many different drugsE l CYP3A4 t b li t i h i– Example: CYP3A4 metabolizes acetaminophen, cocaine, diazepam, testosterone, methadone and many other drugs

• A single drug can be metabolized by many different cP450

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enzymes– Example: acetaminophen is a substrate for CYP1A2, CYP2E1, and

CYP3A4

PHASE II REACTIONS• Phase II reactions are reactions of conjugation – the ase eac o s a e eac o s o co juga o e

transfer of endogenous substances to functional groups of the drug molecule catalyzed by enzymes call transferases to form polar conjugates which are easily eliminated

• Important conjugation reactions include:– Glucuronidation– Glutathione conjugation– Acetylation– Sulfation– Methylation

A i A id C j ti– Amino Acid Conjugation

Example: Phase II Glucuronidation ReactionUDP

UDP-Glucuronic Acid

UDP

COO- COO-

UDPUDP-glucuronyl

transferase

23Substrate DrugGlucuronidated Drug(drug conjugated with glucuronide)

4. EXCRETION:removal of the drug

g

from the body

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EXCRETION OF DRUG FROM THE BODY

M h i f D Eli i ti R l E tiMechanisms of Drug Elimination: Renal Excretion

i l L f di t l collecting

Glomerular Filtration•ALL DRUGS except protein-

secretion b ti

glomerulusproximal

tubuleLoop of Henle

distaltubule

collectingductbound

•Reabsorption = retention•No reabsorption = elimination•Kidney damage = reduced

filtration

secretion reabsorption•Kidney damage = reduced filtration and decreased drug elimination

Tubular Reabsorption

Polar compound

•Across renal tubule cell layers•Active or passive•Requires lipid-solubility

excretion

Lipophilic compound•Requires lipid-solubility•pH-dependent

Active Secretion•Proximal tubule

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Nephron of the kidney•Organic acids•Organic bases•Some drugs

URINE

RENAL ELIMINATION OF WEAK ACIDS AND WEAK BASES

KidneyKidney • All drugs are filtered at the glomerulus• Lipid-soluble drugs are reabsorbed in renal tubules by

i diff ipassive diffusion• Ionized (charged) or hydrophilic drugs can’t be reabsorbed

and are therefore excreted in urine• Alkalization of urine (increasing pH) will facilitate excretion of

weak acids (e.g., aspirin) – is achieved by giving sodium bicarbonate

• Acidification of urine (decreasing pH) will facilitate the excretion of weak bases (e.g., phencyclidine) – is achieved by giving ammonium chloride

Urine BloodpH = 7.4

AHNormal pH (6.0)A- + H+

26A-

p ( )

Higher pH (8.0) RENAL TUBULE CELL LAYER

Weak acids excretion with urine

Mechanisms of Drug Eliminatiion: Biliary Excretion

Drug MetabolismEnterohepaticrecirculation

Excretion ith th fwith the feces

27Other routes of drug elimination include lungs, sweat, and breast milk

ELIMINATION: FIRST-ORDER KINETICSFirst-order kineticsFirst order kinetics• Is described by an exponential function• Elimination is directly proportional to the drug concentration in the body.• Higher drug concentrations = more eliminationg g• Percentage (fraction) of drug eliminated from the body per unit time is

always the same.• MOST DRUGS

Ph i l i l h i ibl f li i ti t t t d• Physiological mechanisms responsible for elimination are not saturated

First-order kineticsNon-linear reduction over time. Same % of drug is eliminated per unit time (e.g., 25%/hr)

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CAPACITY-LIMITED ELIMINATION

• It occurs when drug elimination pathways become saturated

• This process is described by zero-order kinetics• The rate of elimination does not depend on the

concentration of the drug If C >> K then:concentration of the drug. If C >> Km, then:

R t f li i tiVmax C

= V

V i li i ti it K th d

Rate of elimination = Km + C

= Vmax

• Vmax, maximum elimination capacity; Km, the drug concentration at which the rate of elimination is 50% of Vmax; C, concentration of the drug

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ELIMINATION: ZERO-ORDER KINETICSZero order kinetics Capacity limited eliminationZero-order kinetics – Capacity-limited elimination• Is described by a linear function• Rate of elimination is independent of drug concentration in the body• Same amount of drug is eliminated per unit time, regardless of the drug g p g g

concentration in the body.• Physiological elimination pathway becomes saturated (i.e., they reach

capacity)• Is typical of ethanol (over most of its plasma concentration range), and of yp ( p g ),

phenytoin and aspirin at high therapeutic or toxic concentrations• Since elimination is independent of drug concentration, repeated dosing can

result in accumulation and toxicity

Zero-order kineticsLinear reduction in plasma drug concentration over time. Same amount of drug is eliminated per unit time (e g 2 5 mg/hr)

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unit time (e.g., 2.5 mg/hr)

PARAMETERS OF FIRST ORDER KINETICS ELIMINATIONELIMINATION

• Most of pharmacokinetic processes atMost of pharmacokinetic processes at therapeutic concentrations of drugs are not saturated, and follow first order kinetics

• Parameters characterizing first order kinetics elimination– Clearance– Half-life

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CLEARANCE

• Clearance is a pharmacokinetic parameter that predicts the rate of elimination in relation to drug p gconcentration

CL =Rate of elimination

CL Cplasma

• Defined as a volume of fluid from which a drug is removed over a period of time

• Units – volume per unit time: L/min, L/hr

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CLEARANCE

• Rearranging the equation for clearanceg g q

Rate of elimination = CL Cplasma

• The rate of drug elimination is directly proportional to concentration of the drug

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g

HALF-LIFE

• Half-life (t1/2) is the time required to decrease the amount of drug in the body by 50%

•50% of drug is lost in one half life•50% of drug is lost in one half-life•75%% is lost in two half-lives•87.5% is lost in three half-lives•93.75% is lost in four half-lives, etc.93 5% s ost ou a es, etc

HALF-LIVES OF COMMON DRUGS• Procaine: 0.01 hrs• Acetaminophen: 3 hrs• Diazepam: 45 hrs

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• Diazepam: 45 hrs

PHARMACOKINETIC MODELS

• Mathematical modeling of pharmacokinetic processesprocesses– Single-compartment model– Two-compartment model– Multiple compartment models

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PHARMACOKINETIC MODELS• Single-compartment model describes the body as a single• Single-compartment model describes the body as a single

compartment– May accurately describe the kinetics of certain drugs

• Confined to a single (vascular) compartment or• Confined to a single (vascular) compartment, or• Distribution from the vascular compartment into tissues is very

rapid

ka

Absorption

Vd

body

ke

Elimination

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PHARMACOKINETIC MODELS

• Two-compartment model describes the body as central and peripheral (or Blood and Tissues) compartments

• Concentration vs time curve• Concentration vs. time curve– If serum concentration of the drug is plotted using log scale

• It will be a straight line with a single compartment modelIt ill b bi h i li ith t t t d l• It will be a biphasic line with a two-compartment model

n

nc

entra

tioic

sca

le)

Ser

um c

on(lo

garit

hm

37Time (linear scale)

S (