Pharmacokinetics:
Bioavailability
Asmah Nasser, M.D.
Bioavailability

The 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%

Bioavailability
Destroyed
in gut
Oral
Dose
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
Drug dose
at the
systemic
circulation!
3
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
4
Why are oral drugs less
bioavailable?
 Because
they undergo…….
 First
pass metabolism
Hepatic ‘First-pass’ MetabolisM





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 drug
Orally administered drugs will have high
FIRST PASS METABOLISM
Parenteraly administered drugs will bypass
the FIRST PASS METABOLISM to the major extent
Ways to avoid First pass
metabolism?
Sublingual
 IV
 Rectal
 Intramuscular

Bioequailance

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
Summary

◦
◦
◦
◦
◦
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
Summary

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
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Biotransformation
Asmah Nasser, M.D.
Biotransformation

1.
2.

◦
◦
It is a mechanism by which body:
Terminates the action of the drug
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

Phase I

Phase II (addition of subgroups to –OH, NH2, -SH functions in the molecule)
◦
◦
◦
◦
Oxidation
Reduction
Deamination
Hydrolysis
◦
◦
◦
◦
Glucuronide conjugation
Acetylation
Glutathione conjugation
Glycine, methyl and sulfate conjugation
Biotransformation reactions
1.



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
biotransformation




Gender
Genetic predisposition
Co-existing pathological states
Smoking
 Co
administration of other drugs
E.g. FPM of alcohol is lower in women
than in men
 Smoking causes induction of enzymes and
this increases the metabolism of drugs
(e.g. theophylline)

Co-administration of other drugs

Based upon the fact that individual
drugs can have on the drug
metabolizing enzymes two things can
happen:
1. Enzyme induction
2. Enzyme inhibition
Enzyme Induction





Some 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 given
E.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 application

If 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 inhibition
Some drugs can inhibit the drug
metabolizing enzymes
 This can lead to reduced metabolism of
other drugs
 This in-turn leads to increased action
and/or toxic effects of the second drug
 E.g. cimetidine, an anti-ulcer drug is a
potent inhibitor of CYP 3A4. Coadministration of warfarin leads to
increased levels of warfarin and hence
bleeding disorders

List of Enzyme Inducers and
Inhibitors
Toxic 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 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..





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 death
Rx: 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
Summary
Understand CYP-450 system
 Understand the co-administration of
enzyme inducers and inhibitors and their
effects on other drugs
 Understand the concept of a pro-drug
 Tylenol Toxicity, pathophysiology,
treatment
