Biotransformation | Drug metabolism


It refers to a series of chemical alterations of a drug by enzymatic activity occur within the body.

Sites of Biotransformation:


In spite of the fact that every tissue has  capacity to metabolize drugs, the liver is the basic organ of drug metabolism. After oral administration, Some drugs like Isoproterenol, meperidine,  pentazocine, morphine are absorbed from small intestine but go through extensive metabolism in liver by the cytochrome P450 enzymatic system. Drugs are converted from fat soluble to water soluble substances that can be excreted in the urine and bile.


Some orally administered medicines(drugs) similar as clonazepam, chlorpromazine, cyclosporine are well metabolized in intestine than in liver, but others similar as midazolam suffer 50 intestinal metabolism. Some medicines are metabolised by intestinal microorganisms, gastric acids and digestive enzymes, for illustration penicillin, insulin and epinephrine.

Other sites:

Lungs, kidneys, adrenal glands and skin.

Phases of Biotransformation:

  1. Phase I reactions (O.R.H)
  2. Phase II reactions

Phase I Reactions (O.R.H)

What is ORH?

  • Oxidation
  • Reduction
  • Hydrolysis

Phase II Reactions

  • Conjugation

Phase I Reactions:

Phase I reactions is also called enzymatic transformation.

These reactions change drug molecules into more polar water soluble molecules by establishing or unmasking a polar functional group, such as ,-OH, -NH2, -SH. Phase I metabolism may increase, decrease or leave unaltered the pharmacological activity of drugs.


It involves addition of oxygen or removal of hydrogen from the drug.

Cytochrome P-450 dependent (microsomal mixed function oxidase) oxidation:

These reactions are brought about by an enzyme system known as mixed function oxygenase which is located in lipophilic membrane of smooth endoplasmic reticulum of liver and other tissues, it has two components namely NADPH-cytochrome P-450 reductase and cytochrome P-450.

Reaction Example:

  • Aromatic hydroxylation

For example; propranolol,  warfarin

  • Aliphatic hydroxylation

For example; digitoxin, ibuprofen

  • Epoxidation
  • Oxidative dealkylation

For example; paracetamol / acetaminophen

  • S-oxidation

For example; cimitidine

  • N-oxidation
  • Deamination

For example; Diazepam

  • Desulfuration

For example; thiopental

  • Dechlorination

Induction and inhibition of cytochrome P450 drug metabolizing enzymes

Enzyme Induction:

Some drugs induce cytochrome P-450 drug metabolizing enzymes by increasing their synthesis or reducing their degradation, as a result accelerating the metabolism of certain drugs that can lead to their decreased pharmacological effects.

Enzyme inhibition:

Some drugs inhibit cytochrome P450 drug metabolizing enzymes, as a result decreasing the metabolism of certain drugs thereby increasing their pharmacological effects.

Drugs inducing and inhibiting Cytochrome P450

Important inducers:

  • Barbiturates
  • Rifampicin
  • Ethanol
  • Phenylbutazone
  • Phenytoin
  • Carbamazepine

Important inhibitors:

  • Cimitidine
  • Allopurinol
  • Isoniazid (INH)
  • Chloramphenicol
  • Ketoconazole
  • Disulfiram

Cytochrome P-450 independent (non-microsomal) oxidation:

This involves drug oxidation by enzymes found in cytosol or mitochondria of cells.

Reaction examples:

  • Alcohol dehydrogenase converts Ethanol to acetaldehyde.
  • Aldehyde dehydrogenase converts acetaldehyde to acetate.
  • Xanthine oxidase change hypoxanthine to xanthine and xanthine to uric acid.
  • Tyrosine hydroxylase converts tyrosine to dopa.
  • Monoamine oxidase metabolizes catecholamines and serotonin.

Types of mono-amine oxidase (MAO) enzymes

MAO type A:

Present anywhere but mainly in liver, metabolized norepinephrine, serotonin and tyramine.

MAO Type B:

Present mainly in brain, metabolized dopamine.


It occurs in both microsomal and non microsomal metabolizing systems.

Reaction examples:

  • Azo reductions
  • Nitro reductions
  • Carbonyl reductions


It involves non microsomal hydrolase present in various body systems including plasma.

Reactions examples:

  • Esterases
  • Peptidases
  • Phosphatases
  • Amides

Phase II Reactions (Conjugation):

These responses do when phase I metabolities aren't sufficiently polar and can not be readily excreted. In these responses, an endogenous substance( for illustration glucuronic acid, sulphuric acid, acetic acid or amino acid) combines with recently established functional group to form a largely polar conjugate that can be readily excreted.

Reaction examples:

  • Glucuronidation

For example; morphine, paracetamol and diazepam

  • Acetylation

For example; sulfonamides and clonazepam

  • Glutathione Conjugation

For example; ethacrynic acid

  • Glycine Conjugation

For example; salicylic acid

  • Water Conjugation

For example; carbamazepine

  • Methylation

For example; dopamine and norepinephrine

Factors affecting drug metabolism

(For memorization of these factors remember RCD-GAS-DD)

Route of administration:

Oral route can result in extensive first pass effect.

Chemical properties of drugs:

Certain drugs may stimulate or inhibit the metabolism of drugs.


Starvation depletes glycine and alters glycine conjugation.

Genetic factors:

Such as Acetylation of Isoniazid is under genetic control.


Liver cannot detoxify chloramphenicol (an antibacterial agent, inhibitor of protein synthesis in bacteria) in neonates thereby causing grey-baby syndrome.

Sex or gender:

Young males are more susceptible to sedation from barbiturates than females.


Toxic doses deplete enzymes.


Liver diseases decrease drug metabolism and kidney diseases decrease excretion of drugs.

Learn more

What is biotransformation?

What is drug metabolism?

There are how many sites of biotransformation?

Sites of biotransformation

There are how many phases of biotransformation?

Phases of biotransformation

What is phase I metabolism?

What is phase I reactions?

What is ORH?

What is phase II metabolism?

What is phase II reactions?

What is enzymatic transformation?

What is oxidation in metabolism?

What is Cytochrome P450 dependent oxidation ?

What is microsomal mixed function oxidase oxidation?

Reaction examples of Cytochrome P450 dependent oxidation

Induction and inhibition of cytochrome P450 drug metabolizing enzymes

Enzyme Induction

Enzyme inhibition

Drugs inducing and inhibiting Cytochrome P450

Important inducers of cytochrome P450

Important inhibitors of cytochrome P450

What is cytochrome P450 independent oxidation?

What is non-microsomal oxidation?

Reaction examples of cytochrome P450 independent oxidation

There are how many types of mono amine oxidase enzymes

Types of mono-amine oxidase enzymes

What is MAO?

Mono-amine oxidase type A

MAO type A

Mono-amine oxidase type B

MAO type B

What is reduction in metabolism?

Reaction examples of reduction in metabolism

What is Hydrolysis in metabolism

Reaction examples of Hydrolysis in metabolism

What is phase II reactions?

What is Conjugation?

Reaction examples of phase II reactions

Factors affecting drug metabolism

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