## Warfarin-Fluconazole Interaction: CYP2C9 Inhibition **Key Point:** Fluconazole is a potent inhibitor of CYP2C9, the primary enzyme responsible for metabolism of the active S-enantiomer of warfarin. This is the most common and clinically significant mechanism of this interaction. ### Warfarin Metabolism Warfarin is a racemic mixture of S- and R-enantiomers: - **S-warfarin** (active, ~5× more potent): metabolized by **CYP2C9** (~90% of anticoagulant effect) - **R-warfarin** (less active): metabolized by CYP1A2 and CYP3A4 **High-Yield:** Fluconazole selectively inhibits CYP2C9, leading to accumulation of the active S-enantiomer and excessive anticoagulation. ### Mechanism of Interaction ```mermaid flowchart TD A[Fluconazole initiated]:::action --> B[CYP2C9 inhibition]:::outcome B --> C[Reduced S-warfarin metabolism]:::outcome C --> D[Accumulation of active warfarin]:::outcome D --> E[Excessive anticoagulation]:::urgent E --> F[Elevated INR, bleeding risk]:::urgent ``` ### Clinical Pearl This interaction typically manifests within **3–7 days** of fluconazole initiation, as fluconazole reaches steady state and CYP2C9 inhibition becomes maximal. The INR can rise dramatically (as seen in this case: 2.3 → 8.5), creating a high risk of bleeding complications. ### Management | Action | Rationale | | --- | --- | | **Monitor INR closely** | Check within 2–3 days of fluconazole start | | **Reduce warfarin dose** | Often by 30–50% during fluconazole therapy | | **Consider alternative antifungal** | Terbinafine or topical azoles do not inhibit CYP2C9 | | **Educate patient** | Warn of bleeding signs; avoid NSAIDs and other CYP2C9 inhibitors | ### Mnemonic: CYP2C9 Inhibitors ("SICKFACES.COM") **S** – Sulfonamides **I** – Isoniazid **C** – Cimetidine **K** – Ketoconazole, **Fluconazole** **F** – Fluoxetine **A** – Amiodarone **C** – Clarithromycin **E** – Erythromycin **S** – Statins (some) [cite:KD Tripathi 8e Ch 5]
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