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Drug Metabolism and Biotransformation

For medical students2 min readUpdated 2026-10-10

Drug metabolism (biotransformation) refers to the biochemical alteration of pharmaceutical compounds within the body. The primary pathways include oxidation, reduction, hydrolysis, and biosynthetic reactions (conjugation), which attach endogenous substrates to the drug molecule to facilitate elimination.

Key EnzymeCytochrome P-450 mediates microsomal oxidation processes

MAO LocalizationCytosol and mitochondria (non-microsomal oxidation)

HydrolysisCleavage of esters and amides mediated by esterases and amidases

ConjugationAttachment of endogenous substrates to the drug or its metabolites

Oxidation: Microsomal and Non-Microsomal

Oxidation processes of drugs are divided into two major groups based on the localization and type of enzyme systems.

Microsomal oxidation takes place in the endoplasmic reticulum with the direct participation of enzymes. The principal enzyme of this cascade is cytochrome P-450. Key reactions in this pathway include:

Aromatic hydroxylation: Undergone by drugs such as Phenobarbital, phenytoin, propranolol, and warfarin.
Aliphatic hydroxylation: Typical for ibuprofen, barbiturates, tolbutamide, and digitoxin.
N-oxidation: An important biotransformation pathway for Morphinum (morphine), paracetamol, and quinidine.
S-oxidation: Typical for chlorpromazine and cimetidine.
Deamination: Transforms diazepam, ephedrine, and amphetamine.
Dealkylation: Affects Codeinum (codeine), morphine, caffeine, and theophylline.

Non-microsomal oxidation is carried out by cytosolic and mitochondrial enzymes. A classic example of such an enzyme is monoamine oxidase (MAO). Key reactions include:

Oxidative deamination: Characteristic of biogenic amines—epinephrine (adrenaline), norepinephrine, and serotonin.
Aromatic hydroxylation: Substrated by allopurinol.
Decarboxylation: Typical for Levodopa.

Reduction and Hydrolysis

Reduction involves chemical reactions where electrons or hydrogen atoms are added to a drug molecule. Depending on the functional group, variants include:

Reduction of the nitro group: Typical for chloramphenicol and nitrazepam.
Reduction of the carbonyl group: The primary substrate for this reaction is naloxone.
Dehalogenation: Exemplified by the biotransformation of Halothanum (halothane).

Hydrolysis is the cleavage of a drug molecule accompanied by the addition of water. Esterase and amidase enzymes typically mediate these reactions. Substrates undergoing hydrolysis include:

Esters: Acetylsalicylic acid, procaine, suxamethonium bromide, and enalapril.
Amides: Procainamide and indomethacin.

Biosynthetic Reactions (Conjugation)

Conjugation reactions involve attaching various endogenous substrates to the drug molecule or its primary metabolite, rendering the molecule more hydrophilic for subsequent excretion.

Main types of conjugation:

Glucuronidation: Interaction with glucuronic acid, forming glucuronides (esters, thioesters, or amides). Typical substrates: paracetamol, morphine, digoxin, chloramphenicol, and diazepam.
Sulfation: A reaction involving sulfuric acid leading to sulfate formation. Characteristic of paracetamol and steroid hormones.
Glycine conjugation: Salicylic acid is a classic substrate for this pathway.
Glutathione conjugation: Forms glutathione conjugates. Doxorubicin and ethacrynic acid undergo this process.
Acetylation: Attachment of an acetyl group. Typical for Isoniazidum (isoniazid) and sulfonamides.
Methylation: Affects catecholamines (epinephrine, norepinephrine) and captopril.

Frequently asked questions

Which cytochrome P-450 isoenzymes are involved in drug metabolism?

Several CYP isoenzymes are involved in drug metabolism. Key isoenzymes include:

CYP3A4: A key enzyme in the metabolism of numerous medications and antiviral agents.
CYP2C19: Involved in the metabolic activation of clopidogrel.
CYP2E1: Responsible for generating the hepatotoxic metabolite of paracetamol.
CYP1A1 and CYP1A2: Participate in the bioactivation of carcinogens (CYP1A1 is also found in the skin).
CYP2A1 and CYP1B1: Support cutaneous metabolic activity.

What factors influence the rate of drug biotransformation?

Endogenous and exogenous factors affect biotransformation rates, including:

Sex: Male sex hormones can stimulate hepatic microsomal enzyme activity, accelerating the elimination of certain drugs.
Drug interactions: Inducers accelerate metabolism, whereas inhibitors slow it down.
Dietary components: For example, grapefruit juice inhibits certain enzymes, while St. John's wort induces them.
Environmental factors: Cigarette smoke and pollutants induce specific enzymes.

Which drugs are inducers of hepatic microsomal enzymes?

Various pharmacological agents act as enzyme inducers, including:

Phenobarbital: Causes slow-type induction.
Rifampicin: Causes rapid-type induction.
Isoniazid and ethanol: Inductors of the CYP2E1 isoenzyme.
Omeprazole: Pharmacological inducer of CYP1A1 and CYP1A2.
Phenytoin, carbamazepine, dexamethasone, nelfinavir, and efavirenz: Accelerate the metabolism of other drugs.

Which enzymes carry out non-microsomal oxidation?

Cytosolic, mitochondrial, and lysosomal enzymes with high substrate specificity carry out non-microsomal oxidation, involving:

Monoamine oxidase type A (MAO-A): Performs oxidative deamination of biogenic amines (norepinephrine, epinephrine, serotonin).
Alcohol dehydrogenase: A zinc-containing enzyme oxidizing ethanol to acetaldehyde.
Xanthine oxidase: A molybdenum-containing enzyme responsible for hydroxylating purine compounds (allopurinol, theophylline).

What is the purpose of conjugation reactions?

Conjugation attaches endogenous substrates—such as glucuronic acid, sulfuric acid, glycine, or glutathione—to a drug or its metabolites to increase water solubility and promote excretion.

Which enzymes participate in microsomal oxidation?

Endoplasmic reticulum enzymes participate in microsomal oxidation, with cytochrome P-450 playing the predominant role.

What is the difference between reduction and hydrolysis?

Reduction is the addition of electrons or hydrogen atoms to a molecule. Hydrolysis is the cleavage of a molecule accompanied by the addition of water, mediated by esterases and amidases.

Go deeper

Effect of inducers and inhibitors on Cytochrome P-450
Biotransformation characteristics of biogenic amines
Role of monoamine oxidase (MAO) in non-microsomal oxidation
Glucuronidation process and the clinical significance of glucuronides
Pharmacogenetics of acetylation pathways (fast and slow acetylators)