pharmacokinetics: bioavailability asmah nasser, m.d
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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
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