Drug biotransformation involves the chemical alteration of drugs within the body, primarily in the liver, kidney, and intestine. This allows drugs to be converted into forms that can be more easily excreted from the body. The processes of biotransformation are broadly classified into Phase I and Phase II reactions. Phase I reactions introduce or expose functional groups on drugs to make them more polar via oxidation, reduction, hydrolysis, or other reactions. Phase II reactions then conjugate these metabolites to make them water soluble and readily excreted, through conjugation like glucoronidation, acetylation, sulfation, or methylation. Biotransformation can activate prodrugs to their active forms, terminate drug action, produce toxic metabolites,

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DRUG-BIOTRANSFORMATION
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
Dipivefrine→ Epinephrine
Bacampicillin→ Ampicillin
Levodopa→Dopamine
(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.
e.g
Diazepam→Desmethyl Diazepam
Codeine → Morphine
PCM → NAPBQI
Amitriptyline →Nortriptiline
Biotransformation
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
- OH
- NH2
- SH gp
-
Reaction involved:
Oxidation
Reduction
Hydrolysis
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Cyclization
Decyclization
The metabolite of this reaction can be
 active
 Inactive
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.
Oxidation
Chemically defined as
(i)
Addition of oxygen
(ii)
Removal of Hydrogen
(iii)
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
CH3
R
H
N
R
N
CH3
CH3
e.g Drugs undergoing oxidation:
Diazepam/ Barbiturates/ Phenytoin/ Theophylline
Alcohol/ Adrenaline
Hydrolysis
 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
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Cyclization
Formation of a ring structure from a straight chain compound
e.g proguanil.
Decyclization
Minor pathway
 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
readily
 In general, they occur after Phase I reaction. However, they can also occur first
Example
Isoniazid (Phase II) →N-acetyl conjugate
↓ hydrolysis (Phase I)
Isonicotinic acid
excreted
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
(2) Acetylation
(3) Methylation
(4) Sulfate conjugate
(5) Glycine conjugation
(6) Glutathione conjugation
(7) Ribonucleotide/nucleoside synthesis.
Conjugation reactions are highly energy dependent.
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Glucoronide conjugation
 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).
e.g Morphine
Diclofenac
PCM
Digoxin
Sulfonamides
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.
Acetylation
 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
hepatotoxicity.
Glutathione conjugation
 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
↓
Tissue damage
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.
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Sulphate Conjugation
Phenol/ Alcohol/ Aromatic Cpd such as estrone , Paracetamol, Methyldopa, Coumarins
undergoes conjugation with phospho-adenosyl phosphosulphate in the presence of
sulphotransferase.
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.
Microsomal enzyme
 Located on smooth endoplastic Reticulum.
 Primarily in liver /Kidney / intestinal mucosa & lungs
e.g
CyP450/ Mono-oxygenase /Glucoronyl transferase
They catalyse oxidation, Reduction, hydrolysis and Glucoronidation.
NON-Microsomal enzyme
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.
Hoffmann elimination
Refers to inactivation of drugs in body fluid by spontaneous molecular rearrangement
without the need for enzymes.
e.g Atracurium.
References:
th
1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12 ed. US: Mc Graw
Hill.
th
2. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12 ed. US: Mc Graw Hill.
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