Lecture: 5

DRUG METABOLISM/BIOTRANSFORMATION
Metabolism may be defined as the conversion from one chemical form of a substance to
another, different from the parent compound. It is a general term used for chemical
transformation of xenobiotics and endogenous nutrients within or outside the body.
Biotransformation is a specific term used for chemical transformation of xenobiotics in
the living system. Metabolism renders lipid soluble and non-polar compounds to water
soluble and polar compounds so that they can be readily eliminated from the body as lipid
soluble substances are passively reabsorbed from renal or extra renal excretory sites into
the blood by virtue of their lipophillicity.
Xenobiotics are chemical substances that are not nutrient for body (foreign to body).
Examples are: drugs, industrial chemicals, pesticides, polluants, plants and animal toxins.

Functions of Biotransformation:
It performs following functions-
1) Conversion of an active compound to inactive compound (Inactivation)
Phenobarbitone p-hydroxyphenobarbitone

2) Conversion of an active compound to more active compound (Bioactivation)

Malathion Malaoxon

3) Conversion of an inactive compound (prodrug) to active compound (Activation)

Prontosil dye Sulfonamide
Chloral hydrate Trichloroethanol

4) Conversion of an active compound to another equally active compound (no change

in activity)
Digitoxin Digoxin
Phenylbutazone Oxyphenyl butazone

5) Conversion of an active compound to another active compound having entirely

different pharmacological action (change in activity)

Iproniazid (Antidepressant) Isoniazid (Antitubercular)

Drug metabolising enzymes

1) Microsomal Enzymes: Enymes present in smooth endoplasmic reticulum of

liver and other tissues are called microsomal enzymes.

2) Non-microsomal enzymes: Enzymes occurring in organelles/sites other than

endoplasmic reticulum (microsomes) e.g. cytoplasm, mitochondria etc are
called non-microsomal enzymes.

Unit-I Pharmacology Notes by Dr. Pallavi Bhardwaj

 PATHWAYS OF DRUG METABOLISM

1) PHASE-1(NON SYNTHETIC OR NON-CONJUGATIVE PHASE):

It involves addition/unmasking of some reactive functional groups (-OH, -NH2, -

COOH, -SH etc.) to the drugs. The product may be active or inactive.
3 main types of phase I reactions are: oxidation, reduction and hydrolysis.

Unit-I Pharmacology Notes by Dr. Pallavi Bhardwaj

 2) PHASE-II (SYNTHETIC OR CONJUGATIVE PHASE):

It includes reactions that involve attachment of small polar endogenous molecules

like glucuronic acid, sulphate, methyl, amino acids etc. to either unchanged drug or Phase
I products. This increases polarity of the molecule so that it can be easily excreted out
from the body. These reactions generally result in the inactivation of drugs. Conjugates
(endocon + exocon) generally have increased molecular weight and altered physico-
chemical property. The enzymes involved in Phase II reactions are generally called as
transferases.
Some important Phase- II reactions are:

 Glucuronide conjugation (Glucuronidation): Here the conjugating agent is

glucuronic acid. The biological donor of glucuronic acid is Uridine diphosphate
glucuronic acid (UDPGA). If drug contains –OH, COOH, SH, NH2 groups, then it
conjugates glucuronic acid. The reaction is catalyzed by glucuronyl transferase.
The glucuronide product is more water soluble and excreted through kidney.
Examples are morphine, Chloramphenicol etc. Endogenous substrates are bilirubin,
steroids, thyroxine etc.Cat and neonates are deficient of the enzyme glucuronyl
transferase while fish is deficient of UDP.

Unit-I Pharmacology Notes by Dr. Pallavi Bhardwaj

  Sulphate conjugation (Sulfation): Here the conjugating agent is sulfate. The
biological donor of sulfate is 3’-phosphoadenosine-5’-phosphosulphate (PAPS). If
drug contains phenolic hydroxy group, then it conjugates sulphate. The reaction is
catalyzed by sulfotransferase. The sulphate product is more water soluble and
excreted through kidney. Examples are phenol, isoproterenol etc. Pigs are deficient
of the enzyme sulfotransferase.

 Acetyl conjugation (Acetylation): Here the conjugating agent is acetyl coenzyme

A. It drug contains NH2 groups, then it conjugates acetyl coenzyme A. The reaction
is catalysed by acetyl transferase. The conjugated product is lipid soluble
but is also less water soluble, which has greater tendency to precipitate in the renal
tubules. Examples are sulphonamide, isoniazid etc. Acetylation is absent in dogs &
fox, due to deficiency of arylamine acetyltransferase enzyme.

 Methyl conjugation (Methylation): The co-factor for this reaction is S-adenosyl

rnethionine. The reaction is catalyzed by methyl transferase. Norepinephrine
undergoes this reaction to form epinephrine. Methylation reaction differs from
general characteristics of phase II reaction in several ways:
o The metabolites formed are not polar or water soluble.
o The metabolites may have equal or greater activity than parent compound.

 Glutathione conjugation: This conjugtion is catalysed by glutathione-S-

transferase. Glutathione conjugate either due to high molecular weight is excreted
in bile or is further metabolised to form mercapturic acid conjugate that is excreted
in urine. Quinine and acetaminophen undergoes this metabolic reaction.

 Glycine conjugation: Example- Aspirin

 Thiosulphate conjugation: Example: detoxification of cyanide. Thiocyanide

formed is less toxic than cyanide and is excreted out in urine.

FACTORS AFFECTING DRUG METABOLISM

1) Age: In very young and old animals, functional activity of liver is not optimum.
2) Species: Atropine is non-toxic in rabbits due to presence of atropinase.
3) Disease condition: Disease of liver hampers drug metabolism (cirrhosis, hepatitis)
4) Dietary factors: Protein deficiency may affect enzyme production. Diet determines
availability of cofactors like UDP.
5) Drug-drug interactions: Enzyme inhibitors like chloramphenicol and enzyme
inducers like phenobarbitone alters drug metabolism.
6) Genetic differences: genetic polymorphism (slow and fast acetylators)
7) Gender Difference: Some difference in alcohol & oestrogen metabolism in females
as compared to males

Unit-I Pharmacology Notes by Dr. Pallavi Bhardwaj

 8) Hormonal effect: a hypothyroid person has a reduced metabolic activity
9) Temperature: in hot and humid weather metabolism is decreased and vice-versa.
10) Altitude: high altitude low oxygen tension reduce oxidation

Unit-I Pharmacology Notes by Dr. Pallavi Bhardwaj