Drug metabolism

DRUG
METABOLISM

BY MALINA JASAMAI

Kandungan

Introduction 2

Metabolites 3

Factors affecting metabolism 4

Chapter 1



Background Knowledge

v Oxidation & reduction
v Electron withdrawing & electron donating group
v Chemistry of carbonyl compounds; aldehyde, ketone, amide & carboxylic

acid
v Chemistry of alcohol
v Drug absorption & distribution


Aim & Objectives
Ø Discuss the role of metabolism in changing the physical and chemical

characteristics of the drugs

Ø Discuss the metabolic pathways and fate of the metabolites
Ø Describe the factors affecting drug metabolism



References
v Textbook of Organic Medicinal & Pharmaceutical Chemistry, Wilson &

Gisvold’s, Lippincott- Raven.

v An Introduction to Medicinal Chemistry, G.L. Patrick, Oxford University



1

Introduction
v Drugs are exposed to enzyme catalysed reaction which modify their

structure. This is called drug metabolism & can take place in various
tissues (main in the liver)

v The enzymes degrade & modify the foreign compounds (xenobiotic) so it

could be excreted easily.



ENZYME ENZYME

metabolic reaction

DRUG METABOLITE

ENZYME ENZYME lose activity
retain activity
possess different activity



POLAR DRUGS drugs NON POLAR DRUGS

kidney liver

PHASE I PHASE II
conjugation
oxidation
reduction
hydrolysis

DRUG METABOLISM PATHWAYS

2

Metabolites



O OR R = glucuronyl moiety OH

OR O NH
paracetamol
O C5H11
glucuronide conjugate of THC
Active metabolite
Inactive metabolite NO2

O
OPO

O

paraoxon
Toxic metabolite




3

Factors Affecting Drug Metabolism

Species & Strain Differences
v Different animal species may metabolised the same drug differently due to

the presence or absence of a particular metabolising enzyme.
- cats lack of glucoronyltransferase enzymes, therefore tend to conjugate

phenolic drug by sulphation
- pigs lack of sulphotransferase enzymes, therefore tend to conjugate

phenolic drug by glucuronidation
v Different strains of animal may have different amount of the same

metabolising enzymes due to genetic variations
- the cottontail rabbit liver microsomes metabolise hexobarbital about 10

times more rapidly than the New Zealand rabbit liver microsomes.


Hereditary or genetic factors

v The biochemical & morphologic characteristic of living organisms are

genetically controlled thus the synthesis of certain enzymes.



H O
O N NH2
H N
N-acetyltransferase N H
O

N N
isoniazid acetylisoniazid

metabolism of isoniazid

v N-acetyltransferase is genetically determined & the level is higher in rapid
acetylators.
v Varies among different ethnic groups
- Eskimos & Asians - rapid acetylators

- Egyptians - slow acetylators

v The rate at which isoniazid is acetylated is important in terms of
therapeutic response & toxicity
- rapid acetylators - inadequate therapeutic response

- slow acetylators - greater incidence of adverse effects



4

Sex differences
v Up to the age of puberty, the sex variation is not significant. The

differences observed after puberty have been attributed to the production
of androgens and related anabolic steroids which increase the activity of
liver microsomal metabolising enzymes.
- adult male rats metabolise certain drugs much faster than adult female
rats (hexobarbital oxidation)

Enzyme Induction
v The process by which the activity of a metabolising enzyme is increased
increase in the amount of newly synthesised enzymes
- drug metabolism
- duration of drug action
v Concomitant administration of two or more drugs often may lead to
serious drug interactions as a result of enzyme induction
- phenobarbital & warfarin
- phenobarbital & oral contraceptives

Enzyme Inhibition
v Several drugs are capable of inhibiting the metabolism of other drugs

interference with protein synthesis, inactivation of drug metabolising
enzymes & hepatoxicity.
- drug accumulation
- prolonged drug action adverse effects
- phenylbutazone & warfarin

5