It is the chemical alteration of the drug within the body, site of metabolism: liver, kidney,
intestine, Plasma, Lung.
Importance / Consequences of Biotransformation
(1) Activation of Pro-drug:
Enalapril → Enalaprilat
(2) Allows convertion of lipophilic drug to more ionized form & polar form.
Cannot be reabsorbed
Therefore facilitate excretion by kidney
(Termination of action of a drug)
(3) Parent drugs can be converted to less pharmacologically active metabolite (↓ Action).
(4) Biotransformation can lead to formation of active metabolite as well as more toxic
products than the parent molecule.
Codeine → Morphine
PCM → NAPBQI
The processes of biotransformation can be broadly classified as:
Phase I reaction (pre-synthetic reaction)
Phase II reaction (Synthetic reaction)
Phase I reaction
Parent drugs are converted to more polar compounds by introducing or unmasking chemical
groups such as
- SH gp
The metabolite of this reaction can be
Note: When the metabolites are polar enough, they can get excreted readily in urine.
However, in most cases, the phase I metabolites have to undergo some more ( Phase II)
reaction to get eliminated.
Chemically defined as
Addition of oxygen
Removal of Hydrogen
Increase in oxidation state
Microsomal drug oxidation are carried out by an important group of enzyme known as
mixed function oxidase (abundant in microsome of liver).
The final step of the reaction uses NADPH as reducing agent, Molecular oxygen and
Cytochrome P450 reductase.
N.B: CYP 450→ Sluggish catalyst;Therefore reaction is very slow.
e.g De-alkylation oxidation
e.g Drugs undergoing oxidation:
Diazepam/ Barbiturates/ Phenytoin/ Theophylline
Involves addition of water molecule to a drug molecule.
Esters (enzyme involved: Esterase) / Amides ( Amidase)
and Polypeptides (Peptidase) undergo hydrolysis.
The process usually occurs in the liver, intestine or Plasma.
Examples of drugs undergoing Hydrolysis
Procainamide /Procaine/ Lignocaine / Oxytocin/Choline esterase
Formation of a ring structure from a straight chain compound
Involves opening of a cyclic structure.
Example: Phenytoin / Barbiturates.
Phase II reaction (Synthetic Reaction)
Relatively faster than Phase I REACTION.
The metabolites form are mostly inactive and highly ionized that can be excreted
In general, they occur after Phase I reaction. However, they can also occur first
Isoniazid (Phase II) →N-acetyl conjugate
↓ hydrolysis (Phase I)
Usually Phase II reaction involve conjugate of a drug or its phase I metabolite to form polar
compound tha is easily excreted.
Phase II reaction
(1) Glucoronide conjugation
(4) Sulfate conjugate
(5) Glycine conjugation
(6) Glutathione conjugation
(7) Ribonucleotide/nucleoside synthesis.
Conjugation reactions are highly energy dependent.
Importance phase II reaction
Compounds with hydroxyl and carboxy gp are easily conjugated with UDP glucoronic
acid, (derived from glucose in the presence of glucoronyl transferase).
Endogeneous substance e.g Thyroxine / Bilirubin / Steroidal hormone
N.B: Drug glucoronide that are excreted in bile can be hydrolysed by β-glucoronidase
and undergoes enterohepatic recycling
Prolonging duration of activation of such drugs
e.g oral contraceptives.
Substance having Amine/ hydrazine/ residues undergoes acetylation.
Example: Sulfonamides/ hydralazine/ Isoniazid/ Dapsone /PAS/ Clonazepam.
Conjugated with Acetyl COA in presence of N-acetyl transferase
Acetylator status shows genetic polymorphism:
Slow acetylators are prone to neurotoxicity and fast acetylators are proned to
Minor pathway of biotransformation
Drugs containing the following groups are likely to undergo glutathione conjugation:
Epoxides, Hydroxylamine, Cpds containing nitro gp, Oxides.
e.g PCM, Ethacrylic acid / Bromobenzene
When large amount of such intermediated are formed
GSH become deficient
Toxic adducts are formed
Glycine conjugation: (minor pathway)
Drugs that are Acetyl COA derivatives of carboxylic Acid such as
( Salicylates /Nicotinic Acid /Benzoic Acid) gets conjugated with glycine
In the presence of Acetyl COA transferase.
Phenol/ Alcohol/ Aromatic Cpd such as estrone , Paracetamol, Methyldopa, Coumarins
undergoes conjugation with phospho-adenosyl phosphosulphate in the presence of
Methylation Drugs containing catecholamines, Amine and phenol groups like (Adrenaline
/Dopamine/Histamine/Thioroucil) gets methylated with S-aderosyl methionine or cysteine
in presence of transmethylase.
Ribonucleoside/ Nucleotide synthesis
They are important biotransformation reaction for inactivation of many purine/ Pyramidine
anti-metabolites especially cancer chemotherapy agents.
Located on smooth endoplastic Reticulum.
Primarily in liver /Kidney / intestinal mucosa & lungs
CyP450/ Mono-oxygenase /Glucoronyl transferase
They catalyse oxidation, Reduction, hydrolysis and Glucoronidation.
Present in cytoplasm /mitochondria of hepatic cells & other tissues as well as plasma
e.g Oxidases /Esterases/ Amidases.
They catalyse: Oxidation /Reduction/ All conjugation except glucoronidation.
Refers to inactivation of drugs in body fluid by spontaneous molecular rearrangement
without the need for enzymes.
1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12 ed. US: Mc Graw
2. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12 ed. US: Mc Graw Hill.