A patient taking phenytoin for epilepsy is found to have zero-order (saturable) kinetics at therapeutic doses. A dose increase of 20% raises plasma levels disproportionately by 80%. Which pharmacokinetic feature of phenytoin explains this?
- A At therapeutic levels, hepatic CYP2C9/CYP2C19 enzymes are saturated; elimination switches from first-order to zero-order (Michaelis-Menten), so small dose increases cause large rises in plasma concentration ✓
- B Phenytoin has a very narrow therapeutic index but follows linear first-order kinetics at all concentrations
- C Phenytoin undergoes enterohepatic recirculation which is saturated at high doses
- D High plasma protein binding is saturated at therapeutic concentrations, causing free drug to rise exponentially
Correct answer: A. At therapeutic levels, hepatic CYP2C9/CYP2C19 enzymes are saturated; elimination switches from first-order to zero-order (Michaelis-Menten), so small dose increases cause large rises in plasma concentration
Explanation
Phenytoin exhibits saturable (Michaelis-Menten) hepatic metabolism via CYP2C9/CYP2C19. At sub-therapeutic doses, elimination is first-order, but within the therapeutic range the enzymes become saturated and kinetics become zero-order. Consequently, a small increase in dose produces a disproportionately large rise in plasma concentration, making dosing adjustments hazardous and requiring careful monitoring. This is the pharmacokinetic basis for phenytoin's narrow dose-response relationship.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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