A 24-year-old man on phenytoin 300 mg/day has a steady-state level of 12 microgram/mL. His physician increases the dose to 360 mg/day to improve control. Two weeks later he develops nystagmus and slurred speech, and the level is 28 microgram/mL. The pharmacokinetic property responsible is:
- A Autoinduction of CYP3A4 metabolism
- B Dose-dependent increase in oral bioavailability
- C Saturable first-order metabolism leading to zero-order elimination near therapeutic levels ✓
- D Progressive accumulation in adipose tissue
Correct answer: C. Saturable first-order metabolism leading to zero-order elimination near therapeutic levels
Explanation
Phenytoin is metabolised by saturable CYP2B9/CYP2B19 enzymes. Within the therapeutic range the enzymes approach capacity, so clearance falls as concentration rises and elimination shifts toward zero-order kinetics. A modest dose increment therefore produces a disproportionate rise in plasma level and toxicity. Autoinduction is characteristic of carbamazepine, not phenytoin, which eliminates distractor A.
Reference: Katzung Basic and Clinical Pharmacology, 15th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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