Drug Metabolism – Phase-1 and Phase-2

Drug metabolism

The chemical alternation of a drug by the body is termed as drug metabolism, also known as bio transformation. The conversion of drug from one chemical form to another. The main work of drug metabolism is converting liquid soluble (non-polar) drug to water soluble (polar) drug to avoid reabsorption in renal tubules and help in excretion (remove the drug from body).

Most of the drug are lipid soluble (lipophilic), so it can be excreted out through metabolism but some drug are hydrophilic, which is less bio transformed and excreted unchanged.


The drug which convert after metabolism.

Drug Metabolism - Phase-1 and Phase-2

The primary site for drug metabolism is liver and others are kidney, intestine, lungs and plasma. There are different kinds of enzyme system which is present in liver(highest), which bio transform the drug molecules. Enzymes located in the smooth endoplasmic reticulum of the liver and also in other organs such as kidney, lungs etc but in smaller concentration. Mostly bio transformation are done by the microsomal enzymes such as cytochrome p-450 oxidase, glucuronic transferase.


This is the first phase of metabolism when a drug enters the metabolism pathway. This phase yields a drug molecule with the following characteristics.

The molecule form a reactive site or functional group such as: (-OH, -SH or -NH2), which further conjugates with the molecules in phase-2. The process lipophilicity and hydrophilic to facilitate its excretion.

Process of phase-1 metabolism

The drug molecule may undergo any one of the following major processes during phase-1 metabolism. In this, the drugs can be metabolized by oxidation, reduction, hydrolysis and increase polarity of drugs, so drug can easily excrete from kidney. These are non-synthetic reaction and it is a functionalization reaction.

1. Oxidation

These are the most common and important reactions among various phase-1 reaction. The enzymes involved in this reaction are microsomal monooxygenase in liver (cytochrome p450/CYP), CYP(450)s. In this reaction addition of oxygen/removal of hydrogen take place.

2. Hydrolysis

In this process the drug molecule is broken down into similar molecules by the insertion of water molecule.

3. Reduction

This reaction is associated with the introduction of H atoms, addition of hydrogen/removal of oxygen. Drugs containing carbonyl, Nitro and azo group are bio transformed by reductive process. Such reduction generates alcohol and amino moieties in the metabolism.

4. Cyclisation

The process result in the formation of a ring structure from compound arranged in a straight chain. Eg– proguanil

Phase-2 reaction

It is faster than phase-1 and also those not excreted after phase-1 can exerted through phase-2. It involves conjugation with an endogenous substance such as glucuronic acid, sulphate, glycine. These reaction are more polar, so drug can easily excreted by the kidney & liver.

1. Conjugation with glucuronic acid

Glucuronic acid is obtained most commonly from D-glucose. D-glucuronic acid is easily available for combination with functional group like amines, alcohol, acids etc. Glucuronides are commonly produced by all mammals.

2. Conjugation with sulphate moieties

This is a significant step in the metabolism of phenetic compound. Sulphate conjugation is also referred to as ethereal sulphate synthesis.

3. Conjugation with glycine moieties

This is the major pathway involved in the biotransformation of some drugs. Eg- biotransformation of salicylates.

4. Conjugation of acetylation

This configuration yields amide products just like that obtained is conjugation with alpha-amino acid.

Factor affecting drug metabolism.

The following factors play a role in modifying drug metabolism:

1. Inhibitors:- Some drug inhibit the drug metabolizing enzymes & further the drug metabolism as the result the during of action.

2. Age:- In infants and young children drug metabolism enzymes are poorly developed this a drug is poorly metabolism.

3. Species:- Some metabolizing enzymes are present only in a few mammal’s species and are absent in humans. Thus drug metabolized by these enzymes prove to be toxic to humans while they are non-toxic to others.

4. Genetic:- Certain individuals may inherent drug metabolism enzymes deficiency. Eg- genetic deficiency of glucose-6-phosphate, Dehydrogenase (G-6-PD) enzyme result in hemolysis an administering primaquine.

5. Body temperature:- Arise in body temp entices drug metabolism while a decrease in body temperature reduces drug metabolism.

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