Phenytoin displays zero-order (saturation) kinetics at therapeutic doses. A patient at 300mg/day has a plasma level of 10 mcg/mL. When the dose is increased to 350mg/day, the plasma level rises to 25 mcg/mL rather than the expected 11.7 mcg/mL. This non-linear behavior is explained by:

• A Phenytoin at higher doses inhibits its own CYP2C9 metabolism via competitive product inhibition
• B At therapeutic concentrations, CYP2C9/2C19 hydroxylation is saturated; small dose increments dramatically increase plasma levels as Km is approached and elimination switches from first-order to zero-order kinetics ✓
• C Phenytoin absorption becomes concentration-dependent at higher doses due to P-glycoprotein saturation in the gut
• D Higher phenytoin plasma levels saturate albumin binding sites, displacing the drug and greatly increasing free fraction

Explanation

Phenytoin is metabolized by CYP2C9 (primarily) and CYP2C19 by para-hydroxylation (HPPH). This enzymatic process follows Michaelis-Menten kinetics; at sub-therapeutic doses (<<Km), elimination is first-order and dose-proportional. At therapeutic concentrations, phenytoin approaches and then exceeds Km for these enzymes, causing enzyme saturation. Once saturated, elimination rate becomes constant (zero-order), so small dose increments produce disproportionately large plasma level increases. The Km for phenytoin hydroxylation is approximately 4–8 mg/L, well within the therapeutic range (10–20 mg/L). This explains why phenytoin dose adjustments above 300mg/day should be made in 30mg (or smaller) increments.

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

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Written and medically reviewed by the StethoPrep medical team.