Drug-Drug Interactions Affecting Pharmacokinetics

Pharmacokinetic drug-drug interactions (DDIs) occur when one drug alters the absorption, distribution, metabolism, or excretion of another, resulting in clinically significant changes in drug exposure. Unlike pharmacodynamic interactions (additive or antagonistic effects at the same receptor), PK interactions operate through indirect mechanisms and may be delayed, prolonged, or affect drugs not administered simultaneously.

Absorption interactions arise at several levels. Chelation and complexation: antacids, sucralfate, iron, calcium, and magnesium ions form insoluble complexes with fluoroquinolones, tetracyclines, and bisphosphonates, dramatically reducing oral bioavailability. Administration of ciprofloxacin with an antacid may reduce absorption by 80–90%. The clinical solution is to separate administration by at least 2 hours. Alteration of gastric pH: proton pump inhibitors (PPIs) raise gastric pH, reducing dissolution of pH-dependent drugs (itraconazole capsules require acid; ketoconazole absorption greatly reduced). Gut motility: metoclopramide accelerates gastric emptying and may reduce absorption of drugs requiring prolonged gastric residence (some controlled-release formulations), while anticholinergics slow emptying. P-glycoprotein (P-gp) inhibition in the gut wall: P-gp actively effluxes many drugs (digoxin, dabigatran, certain antiretrovirals) from enterocytes back into the gut lumen. P-gp inhibitors (cyclosporin, verapamil, quinidine) block this efflux, substantially increasing oral bioavailability and plasma concentrations.

Metabolism interactions are the most clinically significant category and predominantly involve the CYP450 enzyme family. Enzyme inhibition increases plasma concentrations of substrates. Competitive inhibition is concentration-dependent and rapid in onset. Mechanism-based (irreversible) inhibition requires new enzyme synthesis for recovery. Key inhibitors: clarithromycin and erythromycin (CYP3A4), fluconazole (CYP2C9, CYP3A4), amiodarone (CYP2C9, CYP3A4, CYP2D6), verapamil and diltiazem (CYP3A4), ciprofloxacin (CYP1A2). Enzyme induction increases CYP activity, reducing substrate concentrations. Induction takes days to weeks (new CYP protein synthesis required) and the offset is similarly slow. Key inducers: rifampicin (potent pan-CYP inducer), carbamazepine, phenytoin, phenobarbitone, St John's Wort, efavirenz. Clinically critical induction interactions: rifampicin reduces warfarin levels by 4–5 fold — very high warfarin doses required, then dose must be reduced when rifampicin stopped to avoid supratherapeutic anticoagulation.

UGT interactions: valproate inhibits UGT1A4 and UGT2B7, increasing lamotrigine concentrations by 2-fold — a critical interaction requiring lamotrigine dose reduction. Excretion interactions: NSAIDs reduce renal prostaglandin synthesis, causing afferent arteriolar constriction and reducing GFR — raising levels of renally cleared drugs (lithium, methotrexate, aminoglycosides). Probenecid competitively inhibits OAT-mediated renal secretion of penicillins, methotrexate, and zidovudine. Urinary pH manipulation (ammonium chloride acidifies — reduces amphetamine excretion; sodium bicarbonate alkalinises — increases aspirin excretion). Transporter interactions at the renal tubule: trimethoprim inhibits OCT2-mediated secretion of creatinine and metformin — a documented interaction.