drugmetabolizing

Drug metabolism refers to enzymatic biotransformation of pharmaceuticals and other xenobiotics. It occurs mainly in the liver, but also in the intestinal wall, kidney, lungs, and other tissues. The primary purpose is to convert lipophilic compounds into more water-soluble metabolites to facilitate elimination, reduce pharmacologic activity, and sometimes generate active or toxic products.

Metabolic reactions are typically described in two phases. Phase I introduces or exposes polar functional groups by oxidation, reduction, or hydrolysis, often mediated by cytochrome P450 enzymes (CYPs) such as CYP3A4, CYP2D6, and CYP2C9, as well as flavin-containing monooxygenases and esterases. Phase II conjugates, via transferases such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N‑acetyltransferases (NATs), and glutathione S-transferases, to form highly polar, easily excreted compounds.

Metabolites may be inactive, retain activity, or be toxic. Genetic variation in metabolizing enzymes, especially CYP2D6, CYP2C19, and NAT2, creates interindividual differences in metabolism (poor, intermediate, extensive, or ultra-rapid metabolizers). Drug interactions can arise from inhibition or induction of metabolizing enzymes (e.g., rifampin inducing CYPs; azole antifungals inhibiting them). Age, liver disease, and other factors also affect metabolism.

Clinical implications include altered drug efficacy and risk of adverse effects, dose adjustments, and potential drug interactions. In drug development, metabolism informs clearance and half-life predictions. Laboratory approaches use liver microsomes, hepatocytes, and recombinant enzymes to study metabolism, while in vivo pharmacokinetics assess systemic exposure to parent compounds and metabolites.