An adult epileptic well controlled on phenytoin 300 mg/day has two consecutive subtherapeutic levels. The physician increases the dose to 360 mg/day. Two weeks later the patient returns with nystagmus, ataxia, and slurred speech, and the level is now markedly supratherapeutic. The kinetic property of phenytoin best explaining this abrupt deterioration is:
- A Active secretion into bile followed by enterohepatic recirculation
- B Autoinduction of CYP3A4 leading to accumulation of toxic metabolites
- C Zero-order elimination due to saturation of hepatic metabolism within the therapeutic range ✓
- D Saturable protein binding that reduces free fraction at higher doses
Correct answer: C. Zero-order elimination due to saturation of hepatic metabolism within the therapeutic range
Explanation
Phenytoin follows Michaelis-Menten (capacity-limited) kinetics: hepatic hydroxylation saturates at concentrations within the therapeutic range, so elimination shifts from first-order to zero-order. C modest dose increment then produces a disproportionately large rise in plasma concentration, causing dose-dependent neurotoxicity. Option D is wrong because saturable protein binding would raise the free fraction rather than lower it, and it does not explain total level overshoot.
Reference: Katzung Basic and Clinical Pharmacology, 15th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.