A 30-year-old woman on phenytoin 300 mg/day has a steady-state serum level of 11 mg/L. The dose is increased to 350 mg/day and the new steady-state level is 26 mg/L, with nystagmus and ataxia. This disproportionate rise in concentration is best explained by:
- A Autoinduction of hepatic metabolism increasing clearance
- B Competitive displacement of phenytoin from plasma protein binding sites
- C Saturation of hepatic metabolism so that elimination becomes zero order ✓
- D Dose dependent reduction in renal clearance of unchanged drug
Correct answer: C. Saturation of hepatic metabolism so that elimination becomes zero order
Explanation
Phenytoin follows Michaelis-Menten kinetics. Within the lower therapeutic range the liver can clear almost all delivered drug, but as concentrations approach and exceed the Km for its metabolising enzymes the system saturates and elimination rate becomes fixed, that is zero order. Small dose increments then produce large, unpredictable rises in level, which is why dose changes are made in 25 to 50 mg steps. Autoinduction is a property of carbamazepine, and displacement only transiently raises the free fraction.
Reference: Katzung Basic and Clinical Pharmacology, 15th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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