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?

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. ### Phenytoin Interaction Mechanisms | Mechanism | Example | Clinical Effect | |-----------|---------|------------------| | **CYP2C9 induction** | Warfarin | ↓ INR → loss of anticoagulation | | **CYP3A4 induction** | Oral contraceptives, corticosteroids | ↓ Efficacy → breakthrough bleeding, reduced immunosuppression | | **CYP2C19 induction** | Clopidogrel | ↓ Prodrug activation → reduced antiplatelet effect | | **Protein displacement** | Minimal clinical significance | Not a major mechanism of phenytoin interactions | **High-Yield:** Phenytoin is a classic **enzyme inducer**. Its interactions are dominated by: 1. **CYP450 induction** → ↓ levels of warfarin, oral contraceptives, corticosteroids, methotrexate, theophylline 2. **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): - **S**t. John's Wort, **I**soniazid, **C**arbamazepine, **K**etoconazole (inhibitor, not inducer), **F**enytoin, **A**lcohol (chronic), **C**imetidine (inhibitor), **E**thosuximide, **S**ulfonamides ### 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.