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Drug Biotransformation

For medical students2 min readUpdated 2026-10-10

Biotransformation is the process of chemical modification of drugs within the body, necessary for their subsequent elimination. Xenobiotic metabolism typically proceeds in two phases: chemical modification (most commonly microsomal oxidation) and conjugation.

Main organLiver (also kidneys, intestines, blood plasma)

Enzyme systemEndoplasmic reticulum monooxygenase system

Phase I goalChemical modification (hydroxylation, oxidation, reduction)

Phase II goalBinding (conjugation) to form a polar conjugate

Outcomes of Biotransformation

Following chemical modification, the properties of the drugs change. Three main outcomes are possible:

Drug inactivation. Pharmacological activity decreases (e.g., phenobarbital, ephedrine, nitrites).
Increased activity. More active compounds are formed (e.g., during the metabolism of phenylbutazone, lovastatin, methyldopa, normorphine).
Formation of toxic metabolites. Degradation processes can yield substances with toxic effects (e.g., the breakdown of phenacetin or sulfonamides).

Main Stages of Xenobiotic Detoxification

The process of converting hydrophobic substances into a water-soluble form suitable for excretion generally involves two phases.

Phase I. Chemical Modification Carried out by enzymes of the monooxygenase system (microsomal oxidation). Main reaction types:

Oxidation (hydroxylation): introduction of an OH group. Example: oxidation of barbiturates (a methyl group is converted into a hydroxymethyl group).
Reduction: for example, the nitro group of chloramphenicol is reduced to an amino group.
Hydrolysis: cleavage of the molecule involving tissue hydrolases. Example: the breakdown of aspirin into salicylic and acetic acids.

Phase II. Conjugation Both native drugs and Phase I metabolites can enter this reaction. The process is catalyzed by transferase enzymes. Endogenous molecules (conjugation agents: glucuronic acid, glycine, glutathione, acetate, sulfate) attach to the drug molecule.

Glycine binds via the carboxyl group.
Glucuronic acid binds via the hydroxyl (OH) group.
The acetyl residue binds via the amino group ($NH_2$).

Result: formation of a polar conjugate that is readily eliminated from the body.

Enzyme Induction and the Effect of Ethanol

Detoxification enzymes possess broad substrate specificity. Systematic drug intake (or exposure to poisons) can induce (enhance) the synthesis of monooxygenase system enzymes and transferases. This phenomenon underlies tolerance (habituation): due to accelerated metabolism, the therapeutic effect weakens, requiring an increased drug dose.

Effect of Alcohol Chronic ethanol consumption induces microsomal oxidation enzymes (including cytochrome P450). As a result, patients with chronic alcoholism exhibit a decreased efficacy of drugs and anesthetics during surgery due to their accelerated biotransformation.

Metabolism Examples: Aspirin and Phenobarbital

Inactivation of Phenobarbital (a hydrophobic substance):

Phase I: Hydroxylation involving monooxygenase (cytochrome P450) to form p-hydroxyphenobarbital.
Phase II: Conjugation with glucuronic acid (enzyme: UDP-glucuronosyltransferase). The resulting glucuronide is excreted in the urine.

Inactivation of Aspirin:

Phase I: Hydrolysis of aspirin by tissue hydrolases into salicylic and acetic acids.
Phase II: Salicylic acid undergoes conjugation. It forms either salicuric acid (via glycine attachment by glycine N-acyltransferase) or acyl glucuronide (via UDP-glucuronic acid attachment by UDP-glucuronosyltransferase).

Frequently asked questions

Which specific cytochrome P450 isoforms play a major role in drug metabolism in the human liver?

Based on the referenced sources, a complete list of CYP isoforms playing the primary role in human hepatic drug metabolism cannot be compiled.

The sources explicitly name the following isoenzymes related to metabolism and drug interactions:

CYP3A4 — a key enzyme in the metabolic inactivation of protease inhibitors; drugs of this group inhibit CYP3A4, while ritonavir causes the strongest inhibition of CYP3A4 and is used to slow down the metabolism of the primary drug and prolong its action.
CYP2C19 — participates in the metabolic activation of clopidogrel; omeprazole inhibits CYP2C19, which blocks the conversion of clopidogrel into its active metabolite and reduces antiplatelet activity.
CYP2E1 — induced during chronic alcohol consumption.

Cytochrome P450 isoforms differ in primary structure, substrate specificity, and localization.

What is the molecular mechanism of microsomal oxidation enzyme induction during barbiturate intake?

The induction mechanism consists of barbiturates stimulating the production of enzymes involved in their own detoxification.

Drugs such as phenobarbital (Phenobarbitalum) act as inducers of hepatic microsomal enzymes. They trigger and enhance the synthesis of endoplasmic reticulum monooxygenase system proteins and conjugation enzymes. A phenomenon of autoinduction develops, wherein the drug accelerates its own metabolism and elimination. This leads to rapid drug degradation, a weakening of its therapeutic effect, and the development of pharmacokinetic habituation (tolerance), requiring an increased administered dose.

Why must the dose of a drug often be increased with prolonged use?

Due to enzyme induction. Drugs stimulate the synthesis of monooxygenase system enzymes and conjugation reactions, which accelerates drug metabolism and elimination from the body.

What is the core purpose of Phase II biotransformation?

It is a conjugation reaction. Under the action of transferases, an endogenous group (such as glucuronate or glycine) is attached to the drug molecule or its metabolite, making the substance polar and facilitating its excretion.

Which enzymes perform chemical modification during the first stage?

The endoplasmic reticulum monooxygenase system (specifically cytochrome P450) plays the primary role. Tissue hydrolases are also involved.

How does chronic alcoholism affect drug action?

Chronic ethanol intake induces microsomal oxidation enzymes (cytochrome P450). This accelerates xenobiotic biotransformation, reducing the efficacy of medications and anesthesia.

Go deeper

Mechanisms of isoniazid toxicity: effects on vitamin B6 metabolism
Comparison of phenacetin and paracetamol metabolism
Role of PLP-dependent enzymes in nervous tissue (glutamate decarboxylase)
Ethanol catabolism: alcohol dehydrogenase and microsomal pathways
Specificity of conjugation agent binding (glucuronic acid, glycine, acetyl-CoA)