Biotransformation and Its Clinical Importance

Definition

Biotransformation, or drug metabolism, is the chemical alteration of drugs within the body. This process primarily occurs in the liver and converts lipophilic drugs into more hydrophilic (water-soluble) metabolites, facilitating their excretion.

Phases of Biotransformation

Phase I Reactions (Functionalization Reactions)

- Purpose: Introduce or expose functional groups (e.g., hydroxyl, amine, or carboxyl groups) on the drug molecule.

- Types of Reactions: Oxidation, reduction, and hydrolysis.

- Enzymes Involved: Cytochrome P450 (CYP450) enzymes are key players in oxidation reactions.

- Example: Diazepam undergoes oxidation by CYP450 enzymes to form active metabolites, such as desmethyldiazepam and oxazepam.

Phase II Reactions (Conjugation Reactions)

- Purpose: Increase the water solubility of the drug by conjugating it with hydrophilic molecules.

- Types of Reactions: Glucuronidation, sulfation, acetylation, and methylation.

- Enzymes Involved: Transferases (e.g., UDP-glucuronosyltransferase).

- Example: Morphine undergoes glucuronidation in the liver, forming morphine-6-glucuronide, which is more water-soluble and readily excreted in urine.

Factors Affecting Biotransformation

- Genetic Variability: Genetic polymorphisms in CYP450 enzymes can lead to variations in metabolism, affecting drug efficacy and toxicity.

- Age: Infants and the elderly often have reduced enzyme activity, leading to altered drug metabolism.

- Disease States: Liver diseases, such as cirrhosis, impair drug metabolism, leading to higher drug levels in the body.

- Drug Interactions: Some drugs can induce or inhibit CYP450 enzymes, altering the metabolism of other drugs.

Clinical Importance of Biotransformation

- Activation of Prodrugs: Some drugs are administered in an inactive form (prodrugs) and require biotransformation to produce active metabolites. Example: Codeine is converted to morphine by CYP2D6 to exert its analgesic effects.

- Detoxification and Elimination: Biotransformation aids in drug detoxification and elimination, reducing toxicity.

- Drug-Drug Interactions: Enzyme induction or inhibition can lead to interactions, requiring dose adjustments.

Example of Biotransformation: Acetaminophen

- Phase I (Toxic Pathway): A small fraction of acetaminophen undergoes CYP450 oxidation to form a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).

- Phase II (Detoxification): NAPQI is detoxified by conjugation with glutathione. In overdose situations, glutathione is depleted, leading to liver toxicity.