A 30-year-old man on phenytoin 300 mg/day has a steady-state level of 12 microgram/mL. His doctor increases the dose to 350 mg/day to improve control. Two weeks later he develops horizontal nystagmus and slurred speech. The pharmacokinetic principle that best explains this disproportionate rise in drug level is:

• A Capacity-limited metabolism following Michaelis-Menten kinetics near therapeutic concentrations ✓
• B First-order absorption saturation causing increased bioavailability
• C Autoinduction of hepatic metabolism reducing clearance over time
• D Saturable protein binding displacing phenytoin into tissues

Explanation

Phenytoin is metabolised by CYP2C9 and CYP2C19 by enzymes that approach saturation within the therapeutic range, so clearance falls as concentration rises. Small dose increments can therefore produce large, nonlinear increases in serum level, which is why adjustments are made in 25 to 50 mg steps. Autoinduction is characteristic of carbamazepine, not phenytoin, and saturable binding affects free fraction rather than total level in this way.

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

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Written and medically reviewed by the StethoPrep medical team.