Metabolism & Elimination

Drug metabolism converts lipophilic drugs into more polar, water-soluble metabolites that can be renally excreted. Metabolism occurs primarily in the liver, with contributions from the gut wall, lungs, and plasma.

Phase I reactions introduce or unmask a polar functional group via oxidation, reduction, or hydrolysis. The cytochrome P450 (CYP) superfamily of haem-containing enzymes catalyses most Phase I oxidations. CYP3A4 is the most abundant hepatic CYP isoform (~30% of total), metabolising over 50% of clinically used drugs including midazolam, cyclosporine, simvastatin, and many antiretrovirals. CYP2D6 is polymorphic: approximately 7% of Caucasians are poor metabolisers (PM) carrying loss-of-function alleles, unable to convert codeine to its active metabolite morphine (no analgesia) but at risk of toxicity from drugs normally inactivated by CYP2D6. Ultra-rapid metabolisers (UM) over-express CYP2D6 and may achieve toxic morphine levels from normal codeine doses — a cause of neonatal opioid toxicity when a breastfeeding mother is UM. CYP2C9 metabolises warfarin (S-enantiomer) and many NSAIDs; CYP2C19 metabolises omeprazole and the prodrug clopidogrel (requires CYP2C19 activation — PMs have reduced antiplatelet effect, increasing cardiovascular risk). Prodrug activation: enalapril (prodrug) → enalaprilat (active ACE inhibitor) via hepatic esterases.

Phase II reactions conjugate Phase I metabolites (or directly the parent drug) with endogenous molecules, increasing polarity. Glucuronidation via UDP-glucuronosyltransferases (UGT) is the most common Phase II reaction; morphine-6-glucuronide retains activity. Sulfation is important for paracetamol at therapeutic doses. Acetylation via N-acetyltransferase 2 (NAT2) is polymorphic: slow acetylators (common in Europeans, ~50%) accumulate isoniazid (INH), increasing risk of peripheral neuropathy and hepatotoxicity. Glutathione conjugation detoxifies reactive electrophiles; in paracetamol overdose, CYP2E1 generates the reactive NAPQI metabolite, which overwhelms glutathione stores and causes hepatic necrosis — the rationale for N-acetylcysteine (NAC) treatment.

Enzyme induction occurs when drugs increase CYP expression via nuclear receptor activation. Rifampicin is the archetypal pan-CYP inducer (CYP3A4, CYP2C9, CYP2C19), reducing plasma levels of co-administered drugs including oral contraceptives, anticoagulants, and antiretrovirals. Carbamazepine and St John's Wort are also potent inducers. Enzyme inhibition competitively or irreversibly reduces CYP activity, raising substrate drug levels. Fluconazole inhibits CYP2C9 (raising warfarin levels, bleeding risk) and CYP3A4. Erythromycin inhibits CYP3A4. Grapefruit juice inhibits intestinal CYP3A4 and P-gp, increasing bioavailability of sensitive substrates.

Renal excretion involves three processes: glomerular filtration (proportional to free drug concentration and GFR), active tubular secretion (via OAT and OCT transporters — can exceed GFR), and passive tubular reabsorption (favours lipophilic, unionised drug). Urinary pH manipulation exploits the pH-partition principle: alkalinising urine (sodium bicarbonate) ionises weak acids (e.g. aspirin, phenobarbitone), trapping them in urine and enhancing excretion — useful in salicylate overdose. Probenecid blocks OAT-mediated secretion of penicillin and uric acid. Hepatic clearance depends on hepatic blood flow, intrinsic clearance, and protein binding; high-extraction drugs (e.g. propranolol, lignocaine) are primarily flow-limited.