A 24-year-old man with epilepsy is well controlled on phenytoin 300 mg/day, with a serum level of 12 microgram/mL. His physician increases the dose to 350 mg/day to achieve a 'better' level. Two weeks later he develops nystagmus and ataxia, and the serum level is found to be 28 microgram/mL. The pharmacokinetic property responsible is:
- A Dose-dependent saturation of metabolism leading to zero-order kinetics ✓
- B Autoinduction of hepatic metabolism
- C Displacement from plasma proteins by endogenous substrates
- D Enterohepatic recirculation of the parent compound
Correct answer: A. Dose-dependent saturation of metabolism leading to zero-order kinetics
Explanation
Phenytoin is metabolised by CYP2C9 and CYP2C19 by saturable Michaelis-Menten kinetics. Within the therapeutic range the enzymes approach capacity, so small dose increments produce disproportionately large rises in serum concentration. This is why phenytoin doses are titrated in small steps with level monitoring. Autoinduction is characteristic of carbamazepine, not phenytoin, and protein displacement changes free fraction without raising total concentration this dramatically.
Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.
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