Prof. Hanan Hagar
Pharmacology Department
By the end of this lecture, students should:
 Recognize the importance of biotransformation
 Know the different sites for drug metabolism
 Define the major phase I and phase II metabolic reactions.
 Describe the modulation of liver microsomal enzymes by
inducers and inhibitors
 Mention two drugs that are known as enzyme inducers and
inhibitors.
 Know the impact of first pass metabolism on drug bioavailability.
Definition

Chemical reactions which occur in the body
and lead to change of drugs from lipid soluble
form to water soluble form that is easily
excreted.

Detoxification

Inactivation or termination of drug action

Activation of prodrug.
Organ sites of drug metabolism
 Liver
(the major site).
 Intestinal
 Plasma
 Kidney
 Skin
 Lung
Mucosa and Lumen
Intestinal Mucosa and Lumen
Gut Mucosa


Monoamine Oxidase (MAO).
Sulphatase.
Gut lumen (bacterial flora)


Glucouronidase.
Azoreductase ( N=N).
Plasma
Enzymes
Catechol o-methyl
transferase (COMT)
Esterases
Amidases
substrate
catecholamines
Esters
Local anesthetics
amides
Local anesthetics
Cellular sites of drug metabolism
 Cytoplasm
 Mitochondria
 Lysosomes
 Microsomes
Cytoplasm
e.g. Alcohol dehydrogenase: reduction of
alcohol.
Ethanol  acetaldehyde  acetic acid.
CH3CH2OH CH3CHO  CH3COOH.
Mitochondria
 Monoamine oxidase enzyme (MAO):
oxidation of catecholamines
 Acetylation by N-acetyl transferase:
-
Introduction of acetyl group (CH3COO )
Microsomes
Microsomal enzyme system = mixed
function oxidase = mono-oxygenase =
Cytochrome P-450.
Types of hepatic metabolic reactions
Two phases of hepatic metabolic reactions:
Phase I reactions include:
Oxidation.
 Reduction.
 Hydrolysis.

Phase II reactions include

Conjugation reactions
Microsomal oxidation
Oxidation by cytochrome P450 enzymes
present in microsomes
Non microsomal oxidation
Oxidation by soluble enzymes in cytosol
or mitochondria of cells as oxidases and
dehydrogenases.

Dehydrogenases
◦ Alcohol dehydrogenase
◦ Aldehyde dehydrogenase

Oxidases
◦ Monoamine oxidase (MAO): metabolism of
catecholamines
◦ Xanthine oxidase: metabolism of xanthine
Hypoxanthine  xanthine  uric acid.
uric acid accumulation  GOUT
Reduction reactions
Microsomal
reduction
◦ Nitrobenzene  Aniline.
NO2  NH2
Non
microsomal reduction
◦ Chloral hydrate  Trichloroethanol (active).
CCl 3 - CHO  CCl 3 –CH2OH
Hydrolysis
 All
are non microsomal
 Hydrolysis
occurs by enzymes that are (esterases
or amidases)
 Drugs
(substrates) affected are either esters or
amides
Hydrolysis

Esters as acetylcholine (neurotransmitter).
Acetylcholine choline + acetate.
esterase
R1-COOR2  R1COOH

+ R2OH.
Amides as lidocaine (used as local anesthetic)
amidase
R1 - CONH - R2  R1 - COOH + R2NH2.
Inactivation of drug (termination of action)
 Conversion of active drug to another active
metabolite.
 Conversion of drugs to toxic metabolites.
Paracetamol  hepatotoxic metabolite
 Activation of pro-drug
 Product might undergo phase II.

Phase II Conjugation Reactions
Conjugation of metabolite coming from (phase
I) with endogenous substance as methyl group,
acetyl group, sulphate, amino acid or
glucouronic acid to produce conjugate that is
water soluble and easily excreted.
Types of conjugation reactions
Conjugation reaction
Enzyme required
glucouronide conjugation
Glucouronyl transferase
_
Acetylation (CH3 COO )
Sulphation (SO4
__
)
N-acetyl transferase
Sulfo transferase
Methylation ( CH3 )
methyl transferase
Amino acids conjugation
Glycine conjugation


All are non microsomal except glucouronidation
Glucouronide conjugation is a microsomal
process (the most common).

Deficieny of glucouronyl transferase enzyme in
neonates may result into toxicity with
chloramphenicol (Gray baby syndrome).
 Usually
pharmacologically inactive.
 Polar
 more
water soluble.
 more readily excreted in urine.

Age  rate of metabolism in neonates

Nutrition

Genetic Variation

Diseases ( rate of metabolism in liver diseases)

Gender

Degree of Protein Binding

Enzyme Induction & inhibition
Enzyme Induction & inhibition

Activities of liver microsomal enzymes
may be changed by administration of some
drugs.
 Liver
microsomal enzymes inducers: drugs that
increase activities of liver microsomal enzymes.

Liver microsomal enzymes inhibitors
drugs that decrease activities of liver
microsomal enzymes.
Microsomal inducers Microsomal inhibitors
Alcohol
Cigarette smoking
Phenobarbitone hypnotic
Phenytoin (antiepileptic)
Rifampicin (Anti TB)
Grisofulvin (antifungal)
Grape fruits
Cimetidine
Erythromycin (antibiotic)
Ketoconazole (antifungal)
Enzyme induction may result in:
 increase
metabolism of the inducer drug.
 Tolerance : decrease in its pharmacological
action
 Drug interactions: increase the metabolism
and excretion of co-administered drugs
e.g. phenytoin & oral contraceptives.
 Failure of contraceptive may lead to
pregnancy if combined with phenytoin.

Enzyme inhibition may

Delay the metabolism and excretion of the
inhibitor drug and co-administered drugs.

Prolong the action of the inhibitor drug & coadministered drugs.

e.g. erythromycin & warfarin.

Inhibition of warfarin metabolism may lead to
increase its anticoagulant effect.