A patient on a therapeutic dose of phenytoin develops nystagmus, ataxia, and mental slowing. Phenytoin has a narrow therapeutic window because of its saturable (zero-order) kinetics. Which pharmacokinetic principle best explains why small incremental doses cause disproportionately large rises in plasma phenytoin levels?

• A Phenytoin's high protein binding displaces endogenous compounds at supratherapeutic doses
• B Phenytoin inhibits its own renal secretion at high concentrations
• C Induction of P-glycoprotein by phenytoin paradoxically reduces its distribution volume
• D At therapeutic concentrations CYP2C9 enzymes are saturated, so additional drug causes exponential accumulation ✓

Explanation

Phenytoin exhibits Michaelis-Menten (capacity-limited) kinetics; CYP2C9 and CYP2C19 enzymes that hydroxylate phenytoin approach saturation at the upper end of the therapeutic range (10-20 mcg/mL). Once the metabolizing enzymes are saturated, drug elimination rate becomes fixed (zero-order), meaning any additional dose increment leads to non-proportional, steep rises in plasma concentration. This is why dose adjustments above 300 mg/day must be made in small increments (25-50 mg).

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

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Written and medically reviewed by the StethoPrep medical team.