A patient on long-term phenytoin therapy develops drowsiness and ataxia. Plasma phenytoin level is 32 mg/L (therapeutic range 10-20 mg/kg). The physician reduces the dose by only 100 mg/day (from 400 mg to 300 mg/day). What pharmacokinetic principle explains why a small dose reduction can produce a disproportionately large drop in plasma level?

• A Phenytoin follows Michaelis-Menten (saturation) kinetics, so small dose changes near saturation produce large concentration changes ✓
• B Phenytoin has first-order kinetics at all concentrations
• C Phenytoin clearance decreases with higher doses due to enzyme inhibition
• D Phenytoin undergoes enterohepatic recirculation that is dose-dependent

Explanation

Phenytoin exhibits zero-order (saturation) kinetics at therapeutic and supratherapeutic concentrations because the metabolizing enzyme (CYP2C9) is saturated. At saturation, elimination rate is constant (Vmax) regardless of concentration, so plasma concentration becomes very sensitive to dose changes. B small dose reduction can cause a disproportionate fall in plasma level, which is why dose adjustments must be small (no more than 50-100 mg) to avoid subtherapeutic levels.

Reference: Katzung and Trevor's Pharmacology: Examination and Board Review, 13th ed.

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Written and medically reviewed by the StethoPrep medical team.