A 30-year-old woman on phenytoin has a free serum level of 0.8 microgram/mL. Her physician increases the daily dose by 50 mg. Repeat level after a week is 2.5 microgram/mL, far higher than expected. The kinetic property of phenytoin responsible is:

• A First-order elimination with a very long half-life
• B Displacement from albumin binding sites by endogenous fatty acids
• C Autoinduction of CYP3A4 increasing clearance unpredictably
• D Saturable hepatic metabolism leading to Michaelis-Menten kinetics near the therapeutic range ✓

Explanation

Phenytoin is metabolised by saturable hepatic hydroxylation. Within the therapeutic range the enzymes approach capacity, so elimination shifts from first-order toward zero-order (Michaelis-Menten) kinetics. A small dose increment then produces a disproportionately large rise in plasma concentration, hence the need for small titration steps. Autoinduction is a feature of carbamazepine, not phenytoin, and protein displacement alone would raise total but not free drug levels to this degree.

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

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