A 48-year-old woman on warfarin for atrial fibrillation is started on fluconazole for oesophageal candidiasis. Her INR rises from 2.5 to 8.2 within 5 days. Which is the most common mechanism responsible for this warfarin–fluconazole interaction?

## Warfarin–Fluconazole Interaction: CYP2C9 Inhibition **Key Point:** The most common mechanism of elevated INR when fluconazole is combined with warfarin is **inhibition of cytochrome P450 2C9 (CYP2C9)**, the major enzyme responsible for warfarin metabolism. ### Warfarin Metabolism **High-Yield:** Warfarin is a racemic mixture of S- and R-enantiomers: - **S-warfarin** (more potent): metabolized by **CYP2C9** (major pathway, ~80%) - **R-warfarin** (less potent): metabolized by CYP3A4, CYP1A2, CYP2C19 ### Fluconazole as a CYP2C9 Inhibitor 1. **Mechanism:** - Fluconazole is a **potent inhibitor of CYP2C9** - Blocks metabolism of S-warfarin (the more active enantiomer) - Leads to accumulation of warfarin → increased INR 2. **Onset and severity:** - Onset: 2–5 days (as seen in this case) - Severity: Significant (INR rose from 2.5 to 8.2) - Fluconazole is a **high-risk interacting drug** with warfarin 3. **Clinical consequences:** - Supratherapeutic INR → bleeding risk - Requires INR monitoring and possible warfarin dose reduction ### Comparison of Azole Antifungals and CYP Inhibition | Azole | CYP2C9 Inhibition | CYP3A4 Inhibition | Warfarin Interaction Risk | |-------|-------------------|-------------------|---------------------------| | **Fluconazole** | **Potent** | Moderate | **High** | | **Itraconazole** | Moderate | Potent | Moderate–High | | **Ketoconazole** | Moderate | Potent | Moderate–High | | **Miconazole** | Potent | Moderate | **High** | | **Voriconazole** | Moderate | Potent | Moderate | **Mnemonic:** **CYP2C9 = Warfarin's Highway** — Fluconazole blocks this major route, causing warfarin accumulation. ### Clinical Management **Clinical Pearl:** When fluconazole must be used in a warfarin-treated patient: - Monitor INR closely (every 2–3 days initially) - Consider reducing warfarin dose by 30–50% - Switch to alternative antifungal if possible (e.g., caspofungin, which has no CYP interactions) - Educate patient on bleeding precautions **Warning:** Do NOT assume all azoles have the same interaction potential — fluconazole and miconazole are particularly potent CYP2C9 inhibitors.