Which of the following medications is metabolised to pharmacologically ACTIVE metabolites?

Correct answer: C. Diazepam

• A. Lisinopril is unusual among ACE inhibitors precisely because it is NOT a prodrug and is not converted to an active metabolite — it is active as administered and cleared renally unchanged. Enalapril (→ enalaprilat) and ramipril (→ ramiprilat) are the prodrugs in that class.
• B. Acetaminophen's principal metabolites are inactive glucuronide and sulfate conjugates. Its minor CYP2E1 metabolite NAPQI is toxic rather than therapeutically active, and is normally detoxified by glutathione.
• C. CORRECT. Diazepam undergoes hepatic N-demethylation and hydroxylation to a chain of metabolites that are themselves active — desmethyldiazepam (nordiazepam), temazepam and oxazepam. Desmethyldiazepam has an elimination half-life of 50 to 100 hours, far longer than the parent drug. This is exactly why clinical sedation from oral diazepam can persist well beyond the appointment and why patients must be discharged with an escort and warned not to drive.
• D. Amoxicillin is largely excreted unchanged in the urine and does not depend on active metabolites for its effect.

Note: Actively metabolised drugs worth knowing for dentistry: diazepam → nordiazepam/oxazepam (very long tail), codeine → morphine via CYP2D6 (no analgesia in poor metabolisers, danger in ultra-rapid ones), and midazolam → 1-hydroxymidazolam, which is why midazolam accumulates in renal failure.