Drug Metabolism & Biotransformation

Introduction & purpose

• Biotransformation — enzymatic (rarely spontaneous) chemical alteration of a drug/xenobiotic within the body; alongside excretion it is the principal mechanism for terminating drug action.
• Core rationale — most drugs are lipophilic (so they cross membranes to reach targets) and would be reabsorbed from the renal tubule and accumulate indefinitely; metabolism converts them to more hydrophilic derivatives that resist tubular reabsorption and are excreted in urine or bile.
• Hydrophilic drugs escape metabolism — excreted largely unchanged — e.g. streptomycin, neostigmine, aminoglycosides, quaternary ammonium compounds.
• Four possible outcomes — (1) inactivation (usual — e.g. paracetamol, propranolol); (2) active drug → active metabolite (codeine → morphine; diazepam → oxazepam; losartan → E-3174); (3) activation of an inactive prodrug; (4) active drug → reactive/toxic intermediate (paracetamol → NAPQI).