Pharmacokinetics: Drug Metabolism

Most drugs are hydrophobic to facilitate membrane crossing during absorption, yet must also have sufficient hydrophilicity for distribution and excretion. Drug metabolism solves this by converting lipophilic drugs to water-soluble metabolites. Metabolic products may differ in activity and toxicity from the parent compound.

Drug metabolism occurs primarily in the liver and intestine. Phase I reactions involve oxidation, reduction, or hydrolysis, adding functional groups (-OH, -SH, -COOH, -NH2). Phase II reactions conjugate the drug or Phase I metabolite to another molecule (glucuronide, sulfate, or glutathione), increasing water solubility and enabling renal or biliary excretion.

The cytochrome P450 (CYP) enzyme family is the dominant Phase I system. CYPs account for approximately 80% of oxidative drug metabolism and 50% of total drug elimination. They activate molecular O2 and link it to the drug. Each CYP has substrate specificity — individual enzymes oxidise particular structural features. CYP3A is the most important family, responsible for ~50% of CYP enzyme activity. Major site: liver; minor: small intestine epithelium.

CYP can be inhibited or induced. Induction (e.g. by rifampicin, phenytoin) increases CYP3A expression, reducing plasma concentrations of co-administered drugs by up to 95% — a 2-3 week process requiring dose increases of affected drugs. CYP inhibition (e.g. grapefruit juice inhibits CYP3A4) causes drug accumulation and potential toxicity. Genetic polymorphisms in CYP genes explain interindividual variability.

Major Phase II enzymes: UGTs add glucuronic acid (substrate: UDP-glucuronic acid); SULTs add sulfate (substrate: PAPS — low cellular concentration because its synthesis requires considerable ATP); GSTs add glutathione (GSH — a cellular antioxidant).

When Phase II substrates are depleted, drugs are forced through alternative (shunt) pathways, potentially producing toxic metabolites. The classic example is paracetamol overdose: depletion of PAPS and GSH leads to accumulation of a toxic reactive intermediate (NAPQI) that binds hepatic proteins, causing hepatocellular necrosis.

Pro-drugs are inactive until metabolised (e.g. irinotecan → active SN-38). Drug interactions via CYP inhibition or induction are a major source of clinically significant drug-drug interactions.