Pharmacokinetics: Metabolism and Excretion of

Drugs, Kinetics of Elimination

BIOTRANSFORMATION
(Metabolism)

to render nonpolar (lipid-soluble) compounds polar (lipidinsoluble) so that they are

not reabsorbed in the renal tubules and are excreted

to protect the body from ingested toxins

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The primary site for drug metabolism is liver; others arekidney, intestine, lungs and
plasma

Biotransformation of drugs may lead to the following

Inactivation

Active metabolite from an active drug

Activation of inactive drug

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BITS Pilani, Hyderabad Campus
Biotransformation reactions can be classified into

Nonsynthetic/Phase I/Functionalization reactions

Synthetic/Conjugation/ Phase II reactions

Phase I
A functional group is generated or exposed

Phase I reactions usually convert the parent drug to a more polar metabolite
by introducing or unmasking a functional group (OH, NH2, SH).

Often these metabolites are inactive, although in some instances activity is

only modified or even enhanced.

Phase II
An endogenous radical is conjugated to the drug

Metabolite is mostly inactive

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Nonsynthetic reactions

Oxidation

Addition of oxygen/negatively charged radical or removal of hydrogen/positively

charged radical

hydroxylation; oxygenation at C, N or S atoms; N or O-dealkylation, oxidative

deamination, etc

the initial insertion of oxygen atom into the drug molecule produces short lived highly
reactive quinone/epoxide/superoxide intermediates which then convert to more stable
Compounds

mostly carried out by a group of monooxygenases in the liver

the final step involve a cytochrome P-450 haemoprotein, NADPH, cytochrome P-450
reductase and molecular O2

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BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
CYP-450

R-H + O2 + 2e- + 2H+ R-OH + H2O

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BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
Reduction

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BITS Pilani, Hyderabad Campus
Hydrolysis

This is cleavage of drug molecule by taking up a molecule of water.

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BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
Cyclization

This is formation of ring structure from a straight chain compound, e.g. proguanil

Decyclization

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Synthetic reactions

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BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
Objectives

To terminate the pharmacological effect of the molecule

Make the molecule so water-soluble that it cannot escape clearance, preferably by more than one
route to absolutely guarantee its removal

Mechanisms

Changing the molecular shape so it no longer binds to its receptors

Changing the molecular lipophilicity to hydrophilicity to ensure high water solubility

Making the molecule larger and heavier, so it can be eliminated in bile as well as urine

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Glucuronidation

UDP (uridine diphosphate) glucuronosyl transferases, or UGTs

Endoplasmic reticulum membrane

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BITS Pilani, Hyderabad Campus
Sulphation

Sulphotransferases (SULTs)

the liver, small intestine, main intestine and colon

They are all cytosolic enzymes

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BITS Pilani, Hyderabad Campus
The GSH system

this is based on a three amino acid (cysteine, glycine and glutamate) thiol known as glutathione, or
GSH

Thiols in general are extremely effective at reducing and thus quenching highly reactive,
electrophilic species

GSH has a very high redox potential of -0.33, and donates electrons to reactive
Species

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glutathione-S-transferases

provide the essential active promotion of GSH reaction with electrophilic

Agents

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Role of GSH in
metabolism of
paracetamol

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BITS Pilani, Hyderabad Campus
Stereoisomers of a drug may be metabolized differently and at different rates, e.g.
S-warfarin rapidly undergoes ring oxidation, while R-warfarin is slowly degraded by
sidechain reduction

Only a few drugs are metabolized by enzymes of intermediary metabolism, e.g.

alcohol by dehydrogenase, allopurinol by xanthine oxidase

Majority of drugs are acted on by relatively nonspecific enzymes which are directed
to types of molecules rather than to specific drugs

The same enzyme can metabolize many drugs

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The drug metabolising enzymes are divided into two types

Microsomal enzymes

These are located on smooth endoplasmic reticulum

primarily in liver, also in kidney, intestinal mucosa and lungs

e.g monooxygenases, cytochrome P 450, glucuronyl transferase

They catalyze most of the oxidations, reductions, hydrolysis and glucuronide

conjugation.

Microsomal enzymes are inducible by drugs, diet and other agencies

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Nonmicrosomal enzymes

These are present in the cytoplasm and mitochondria of hepatic cells as well as in
other tissues including plasma

flavoprotein oxidases, esterases, amidases and conjugases are nonmicrosomal

oxidations and reductions, many hydrolytic reactions and all conjugations except
Glucuronidation

The nonmicrosomal enzymes are not inducible but many show genetic polymorphism

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Both microsomal and nonmicrosomal enzymes are deficient in the newborn, especially
premature, making them more susceptible to many drugs, e.g. chloramphenicol, opioids

This deficit is made up in first few months, more quickly in case of oxidation and other
phase I reactions than in case of glucuronide and other conjugations taking 3 or more
months

The amount and kind of drug metabolizing enzymes is controlled genetically and is also
altered by environmental factors

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Effect of genetic
polymorphism

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BITS Pilani, Hyderabad Campus
BITS Pilani, Hyderabad Campus
Effect of diet and
environmental factors

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INHIBITION OF DRUG METABOLISM

One drug can competitively inhibit the metabolism of another if it utilizes the same
enzyme or cofactors

A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme
e.g. quinidine is metabolized by CYP3A4 but inhibits CYP2D6

most drugs, at therapeutic concentrations, are metabolized by non-saturation kinetics,

i.e. the enzyme is present in excess

Clinically significant inhibition of drug metabolism occurs in case of drugs having

affinity for the same isoenzyme
if they are metabolized by saturation kinetics
if kinetics changes from first order to zero order over the therapeutic range

enzyme inhibition has a fast time course (within hours) compared to enzyme induction

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acute interactions of terfenadine (a second-
generation antihistamine) with a CYP3A4
substrate inhibitor (ketoconazole,
erythromycin, or grapefruit juice) resulted in
fatal cardiac arrhythmias (torsades de pointe)
requiring its withdrawal from the market

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 MICROSOMAL ENZYME INDUCTION

Different inducers are relatively Type 2 nuclear receptor like pregnane X receptor (PXR) ,
Constitutive androstane receptor (CAR), peroxisome proliferator
selective for certain cytochrome activator receptor (PPAR)
P-450 enzyme families

phenobarbitone, rifampin,
glucocorticoids induce CYP3A

Phenobarbitone also induces

CYP2B1 and rifampin also induces
CYP2D6

Isoniazid and chronic alcohol

consumption induce CYP2E1

Polycyclic hydrocarbons induce

CYP1A
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BITS Pilani, Hyderabad Campus
Consequences of microsomal enzyme induction

Decreased intensity and/or duration of action

Increased intensity of action of drugs that are activated by metabolism

Tolerance

Some endogenous substrates (steroids, bilirubin) are also metabolized faster

Precipitation of acute intermittent porphyria

Intermittent use of an inducer may interfere with adjustment of dose of another drug
prescribed on regular basis

Interference with chronic toxicity testing in animals

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Possible uses of enzyme induction

Congenital nonhaemolytic jaundice: It is due to deficient glucuronidation of bilirubin;

phenobarbitone hastens clearance of jaundice

Cushings syndrome: phenytoin may reduce the manifestations by enhancing

degradation of adrenal steroids

Chronic poisonings: by faster metabolism of the accumulated poisonous substance

Liver disease

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Diseases Affecting
Drug Metabolism

alcoholic hepatitis, active or

inactive alcoholic cirrhosis,
hemochromatosis, chronic active
hepatitis, biliary cirrhosis, and
acute viral or drug-induced
hepatitis.

cardiac disease, by limiting blood

flow to the liver, may impair
disposition of those drugs whose
metabolism is flow-limited

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FIRST PASS (PRESYSTEMIC) METABOLISM

This refers to metabolism of a drug during its passage from the site of absorption into
the systemic circulation

Attributes of drugs with high first pass metabolism

Oral dose is considerably higher than sublingual or parenteral dose

There is marked individual variation in the oral dose due to differences in the
extent of first pass metabolism.

Oral bioavailability is apparently increased in patients with severe liver disease

Oral bioavailability of a drug is increased if another drug competing with it in first

pass metabolism is given concurrently

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