Pharmacokinetics:Pharmacokinetics:BioavailabilityBioavailability

Asmah Nasser, M.D.

BioavailabilityBioavailabilityThe fraction of the administered dose reaching the

systemic circulation in its chemically unchanged form. Labelled as “F”

Bioavailability of a drug administered IV: 100% Bioavailability of a drug via other routes: ranges from 0% to 100%

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BioavailabilityBioavailability

Oral Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

Drug dose at the systemic circulation!

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How is bioavailability measured?How is bioavailability measured?

To measure bioavailability, drug plasma levels

are measured at different time points following

various routes of administration

Plasma levels are plotted against time

Area under the curve (AUC) is measured

If oral and iv doses are the same, then

F = AUCoral/ AUCiv

Why are oral drugs less Why are oral drugs less bioavailable?bioavailable?

Because they undergo…….

First pass metabolism

Hepatic ‘First-Pass’ Hepatic ‘First-Pass’ MetabolismMetabolism

Metabolism of drug by liver before drug reaches systemic circulation

Drug absorbed into portal circulation, must pass through liver to reach systemic circulation

Reduce the bioavailability of drugOrally administered drugs will have high FIRST

PASS METABOLISMParenteraly administered drugs will bypass

the FIRST PASS METABOLISM to the major extent

Ways to avoid First pass Ways to avoid First pass metabolism?metabolism?SublingualIVRectalIntramuscular

BioequailanceBioequailance Two different formulations or two different brands (brand

A and B) of a same drug give orally to the same person

If they differ in bioavailibility and rate of absorption …both

brand A and B are said to be Bioinequivalent…..this is

common

If they have same bioavailibility and rate of absorption …

both brand A and B are said to be Bioequivalent…..this is

uncommon

SummarySummary Bioavialability refers to

◦ The fraction of drug that reaches the systemic circulation as active metabolite

◦ The fraction of drug that reaches the systemic circulation as intact drug

◦ The fraction of drug that undergoes first pass metabolism

◦ The fraction of drug that eliminated by first pass metabolism

◦ The fraction of drug absorbed from the site of administration

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SummarySummary

Bioavailability

First pass effect (metabolism)

Bioequivalence

Orally administered drugs will have high FIRST

PASS METABOLISM

Parenteraly administered drugs will bypass the

FIRST PASS METABOLISM to the major extent

BiotransformationBiotransformationAsmah Nasser, M.D.

BiotransformationBiotransformation It is a mechanism by which body:1. Terminates the action of the drug2. Sometimes leads to activation of drugs

(pro-drugs) Most drugs are lipid soluble which

means◦ Favorable for absorption◦ Slow removal from the body

3. Biotransformation hastens the excretion by making drugs less lipid soluble

Types of metabolic reactions Types of metabolic reactions Phase I

◦Oxidation◦Reduction◦Deamination◦Hydrolysis

Phase II (addition of subgroups to –OH, -NH2, -SH functions in the molecule)◦Glucuronide conjugation◦Acetylation◦Glutathione conjugation◦Glycine, methyl and sulfate conjugation

Biotransformation reactionsBiotransformation reactions1. Cytochrome P-450 mixed function

oxidases (shortly called as CPY-450 enzymes)

This is the largest enzyme responsible for biotransformation of drugs

The CYP-450 superfamily is in turn subdivided into sub families CYP-1, 2, 3 etc.

They are in turn again subdivided into CYP-1A, 3C etc.

Factors affecting Factors affecting biotransformationbiotransformationGenderGenetic predispositionCo-existing pathological statesSmoking Co administration of other drugsE.g. FPM of alcohol is lower in women than

in menSmoking causes induction of enzymes and

this increases the metabolism of drugs (e.g. theophylline)

Co-administration of other drugsCo-administration of other drugs Based upon the fact that individual

drugs can have on the drug metabolizing enzymes two things can happen:

1. Enzyme induction2. Enzyme inhibition

Enzyme InductionEnzyme InductionSome drugs induce (increase the levels) the

drug metabolizing enzymes This will lead to increased rate of metabolism

of other drugs This in turn will lead to decreased therapeutic

effect of the second drug givenE.g. rifampin is an anti TB drug, it is a known

enzyme inducer (increase the drug metabolizing enzymes)

Examples of drugs known to induce enzymes: carbamazepine, phenobarbital, phenytoin, rifampin

Clinical applicationClinical applicationIf oral contraceptives (OCP) are given to a

lady who is on rifampin then the increase in the enzyme levels will lead to faster metabolism of the OCP and may lead to failure in contraception.

Enzyme inhibitionEnzyme inhibitionSome drugs can inhibit the drug

metabolizing enzymesThis can lead to reduced metabolism of

other drugsThis in-turn leads to increased action

and/or toxic effects of the second drugE.g. cimetidine, an anti-ulcer drug is a

potent inhibitor of CYP 3A4. Co-administration of warfarin leads to increased levels of warfarin and hence bleeding disorders

List of Enzyme Inducers and List of Enzyme Inducers and InhibitorsInhibitors

Toxic metabolismToxic metabolism

Drug metabolism does NOT always lead to drug inactivation

Some drugs can be converted to its active/toxic forms after metabolism

The toxic substances thus produced can lead to severe injury of organs

Acetaminophen metabolismAcetaminophen metabolism

Usually acetaminophen is conjugated to harmless glucuronide and sulfate metabolites

In large doses Phase II metabolic pathways dominate and CYP-450 dependent system converts acetaminophen to a reactive metabolite (N-acetyl-p-benzoquinoneimine)

Contd..Contd..This reactive intermediate is conjugated

with glutathione to a third harmless product

In overdoses the glutathione store gets depleted, so the reactive intermediate combines with essential hepatic cell proteins

This leads to cell deathRx: administration of sulf-hydryl donors

(n-acetylcycteine)Note that ethanol intake induces the

phase-I drug metabolizing enzymes and increases the formation of reactive intermediate of acetaminophen

SummarySummaryUnderstand CYP-450 systemUnderstand the co-administration of

enzyme inducers and inhibitors and their effects on other drugs

Understand the concept of a pro-drugTylenol Toxicity, pathophysiology,

treatment