A patient receives oral phenytoin 300 mg/day and achieves a steady-state level of 12 microgram/mL. When the dose is increased to 400 mg/day, the level rises to 28 microgram/mL and signs of toxicity appear. The kinetic property responsible is:

• A Saturable metabolism leading to zero-order (Michaelis-Menten) kinetics at therapeutic concentrations ✓
• B First-order elimination with a very short half-life
• C Autoinduction of hepatic metabolism increasing clearance over weeks
• D Extensive enterohepatic recirculation prolonging absorption

Explanation

Phenytoin is metabolised by CYP2C9 and CYP2C19 via saturable enzymes. Within the therapeutic range the hepatic enzymes approach capacity, so small dose increments produce disproportionate rises in plasma concentration, which is classic Michaelis-Menten behaviour. Autoinduction is characteristic of carbamazepine, not phenytoin, and would lower levels rather than raise them. Enterohepatic cycling affects absorption timing, not steady-state proportionality. Dose changes in phenytoin should therefore be made in small increments with level monitoring.

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

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