Question
Briefly describe drug biotransformation. Describe microsomal enzyme induction. (4+4)
Answer
a) Drug biotransformation Biotransformation is the enzymatic conversion of a drug into a more polar, generally inactive, and more readily excretable form, occurring mainly in the liver.
- Phase I (functionalization) reactions — oxidation, reduction, or hydrolysis, mainly via the cytochrome P450 system, introduce or expose a reactive functional group; may activate, inactivate, or (occasionally) not change activity.
- Phase II (conjugation) reactions — attach an endogenous substrate (glucuronic acid, sulfate, acetyl group) to the drug or its phase I metabolite, almost always producing an inactive, polar, readily excreted product. Glucuronidation is the most important quantitatively.
Most drugs undergo phase I then phase II sequentially, though the order is not fixed (isoniazid is acetylated before phase I oxidation).
b) Microsomal enzyme induction Certain drugs (Rifampicin, Phenytoin, Carbamazepine, Phenobarbitone, chronic alcohol) increase the synthesis of microsomal (CYP450) enzymes, accelerating metabolism of themselves (autoinduction) and other co-administered drugs.
Onset: takes days (4-14 days to peak), since it requires new protein synthesis; reversal after stopping the inducer takes 1-3 weeks.
Consequences: reduced efficacy of drugs inactivated by metabolism (rifampicin causing oral contraceptive failure), increased toxicity of drugs whose toxic metabolite is overproduced (paracetamol hepatotoxicity worsened in chronic alcohol users via CYP2E1 induction), tolerance via autoinduction (carbamazepine), precipitation of acute intermittent porphyria. Used therapeutically: phenobarbitone accelerates bilirubin conjugation in neonatal jaundice.