A 30-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 better control. Two weeks later he returns with diplopia and drowsiness. The most likely explanation for this disproportionate rise in toxicity is:

• A Autoinduction of CYP2C9 by phenytoin increasing its own clearance
• B Displacement of phenytoin from plasma proteins producing a toxic free fraction
• C Dose-dependent saturation of hepatic metabolism leading to zero-order elimination kinetics ✓
• D Cumulative inhibition of hepatic microsomal enzymes by a phenytoin metabolite

Explanation

Phenytoin is eliminated by saturable metabolism: within the therapeutic range the hepatic hydroxylation approaches Vmax, so small dose increments produce disproportionately large rises in serum concentration (zero-order, Michaelis-Menten kinetics). This is why increments are made in 25 to 50 mg steps with level monitoring. Autoinduction is a feature of carbamazepine, not phenytoin, which rules out option A.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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