The Michaelis-Menten kinetics of phenytoin mean that it shows zero-order kinetics at therapeutic concentrations. What is the clinical implication of this saturation pharmacokinetics?

• A Small dose increments above the Km concentration produce disproportionately large increases in plasma concentration, risking toxicity ✓
• B Small dose increments produce proportionally small and predictable increases in plasma levels
• C Phenytoin half-life is constant at all concentrations, making dosing straightforward
• D Loading doses are unnecessary because phenytoin reaches steady state slowly regardless of dose

Explanation

When plasma phenytoin concentrations approach and exceed the Km (the substrate concentration at half-maximal enzyme velocity, approximately 5–10 mg/L), hepatic CYP2C9 is saturated and the drug switches from first-order (concentration-dependent) to zero-order (concentration-independent) elimination. At this saturation point, a small increase in dose produces a disproportionately large rise in plasma concentration—risking nystagmus, ataxia, and encephalopathy. Half-life is not constant; it lengthens as concentration rises. Monitoring plasma levels and making only small (50 mg) dose adjustments in the therapeutic range are essential to avoid toxicity.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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