A 62-year-old woman on phenytoin for epilepsy, warfarin for atrial fibrillation, and oral contraceptives for hormone replacement is counselled about drug interactions. Which statement about phenytoin interactions is NOT correct?
A. Phenytoin metabolism is saturable, and small dose increases can cause disproportionate increases in serum levels
B. Phenytoin is highly protein-bound and displaces other protein-bound drugs, increasing their free fraction
C. Phenytoin induces CYP2C9, reducing warfarin efficacy and necessitating higher warfarin doses
D. Phenytoin induces CYP3A4, reducing oral contraceptive efficacy and increasing breakthrough bleeding risk
Explanation
Phenytoin Drug Interactions: Mechanism and Clinical Significance
Key Point
Phenytoin is a potent inducer of hepatic metabolism (CYP2C9, CYP3A4, CYP2C19) and affects drug interactions primarily through enzyme induction, NOT protein displacement. While phenytoin is highly protein-bound (~90%), protein displacement is NOT a major mechanism of its clinically significant interactions.
Saturable kinetics → non-linear pharmacokinetics (Michaelis-Menten); small dose increases cause disproportionate serum level rises
3.
NOT protein displacement → this is NOT a clinically significant mechanism for phenytoin
Mnemonic
SICKFACES.COM (drugs that induce CYP450):
St. John's Wort, Isoniazid, Carbamazepine, Ketoconazole (inhibitor, not inducer), Fenytoin, Alcohol (chronic), Cimetidine (inhibitor), Ethosuximide, Sulfonamides
Why Protein Displacement Is NOT the Main Mechanism
While phenytoin is 90% protein-bound, protein displacement interactions are:
Transient — the displaced drug is quickly metabolized or redistributed
Clinically minor — the free fraction increase is usually <10–20% and self-limiting
Not the primary cause of phenytoin's major interactions
Instead, phenytoin's interactions are driven by enzyme induction, which:
Persistent — lasts days to weeks after phenytoin initiation/withdrawal
Clinically major — can reduce interacting drug levels by 30–70%
Requires dose adjustment of warfarin, oral contraceptives, and other substrates
Clinical Pearl
When phenytoin is started in a patient on warfarin, the INR typically drops over 1–2 weeks as CYP2C9 induction increases warfarin metabolism. Warfarin dose must be increased by 20–50% to maintain therapeutic INR.
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