A patient on phenytoin 300 mg/day has a serum level of 12 mcg/mL with good control. The physician increases the dose to 330 mg/day. Two weeks later the level is 25 mcg/mL and the patient is ataxic. The kinetic property of phenytoin responsible is:

• A First-order elimination that accelerates with rising plasma concentration
• B Enterohepatic recirculation prolonging its terminal half-life
• C Autoinduction of CYP3A4 leading to accumulation of active metabolites
• D Saturable hepatic metabolism causing zero-order kinetics within the therapeutic range ✓

Explanation

Phenytoin is metabolised by saturable hydroxylation with a Km close to therapeutic concentrations. Once the enzyme system approaches capacity, small increments in dose produce disproportionate rises in steady-state level because elimination shifts from first order toward zero order. This is classic Michaelis-Menten behaviour and is why doses are adjusted in 25 to 50 mg steps. Autoinduction is a property of carbamazepine, not phenytoin, and enterohepatic cycling does not explain nonlinear kinetics.

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

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