Drug Metabolism & Biotransformation

Drug Metabolism & Biotransformation

1. Definition, purpose & overview

• Biotransformation = chemical alteration of a drug (or any xenobiotic) within the body by enzymatic (rarely spontaneous) reactions; the principal mechanism—alongside excretion—for terminating drug action (KDT 8e Ch.3, pp.28–9).
• Core physicochemical rationale: most drugs and xenobiotics are lipophilic (so they can diffuse across lipid bilayers to reach their targets); lipophilic compounds are readily reabsorbed from the renal tubule and would accumulate indefinitely without metabolism. Biotransformation converts them to more hydrophilic derivatives that resist tubular reabsorption and are eliminated in urine or bile (G&G 14e Ch.5, pp.101–2; KDT 8e Ch.3, p.28; Katzung 16e Ch.4, pp.57–8).
• Xenobiotic = a substance foreign to the body (drugs, dietary phytochemicals, environmental pollutants, food additives, agrochemicals, cosmetics). Drug-metabolizing enzymes are more correctly xenobiotic-metabolizing enzymes; they evolved to detoxify dietary plant toxins (phytoalexins) and also handle endogenous substrates (bilirubin, steroid hormones, catecholamines, bile acids) (G&G 14e Ch.5, p.101).
• Hydrophilic drugs largely escape metabolism and are excreted unchanged, e.g. streptomycin, neostigmine, pancuronium, aminoglycosides, quaternary ammonium compounds (KDT 8e Ch.3, p.28).
• Four possible outcomes of biotransformation (KDT 8e Ch.3, pp.29–30; Katzung 16e Ch.4, p.58):
  • Inactivation — active drug → inactive/less-active metabolite (the usual outcome), e.g. ibuprofen, paracetamol, lidocaine, chloramphenicol, propranolol (and its active metabolite 4-hydroxypropranolol).
  • Active drug → active metabolite — net effect = parent + metabolite(s), e.g. codeine → morphine; procainamide → N-acetylprocainamide; diazepam → desmethyldiazepam/oxazepam; imipramine → desipramine; amitriptyline → nortriptyline; spironolactone → canrenone; losartan → E-3174; digitoxin → digoxin (KDT 8e Ch.3, p.29).
  • Activation of an inactive drug (prodrug) — see §9.
  • Active drug → reactive/toxic intermediate — e.g. paracetamol → NAPQI; benzo[a]pyrene → carcinogenic epoxide (Katzung 16e Ch.4, p.58; Shargel 8e Ch.6, Table 6-2).
• Why biotransformation makes drug development slow/costly: species differences in enzyme expression (limits animal-model prediction), interindividual variation, drug–drug interactions (DDIs), and metabolic activation to toxic/carcinogenic derivatives (G&G 14e Ch.5, p.101).