A 58-year-old man with atrial fibrillation on warfarin (INR 2.5) presents to the clinic. He was recently started on fluconazole 400 mg daily for oral candidiasis. Two weeks later, his INR is 4.8 and he reports spontaneous bruising on his arms. What is the mechanism of this drug interaction?

Explanation

## Drug Interaction Mechanism **Key Point:** Fluconazole is a potent inhibitor of CYP2C9, the primary enzyme responsible for warfarin metabolism. This inhibition leads to decreased warfarin clearance, elevated plasma concentrations, and increased anticoagulant effect. ## Warfarin Metabolism & CYP2C9 Warfarin is metabolized via two pathways: - **S-warfarin** (more potent): CYP2C9 → major route (~90% of anticoagulant effect) - **R-warfarin** (less potent): CYP2C8, CYP3A4, CYP1A2 Fluconazole's selective inhibition of CYP2C9 disproportionately affects S-warfarin elimination. ## Clinical Presentation in This Case | Finding | Explanation | |---------|-------------| | INR rise from 2.5 → 4.8 | Increased warfarin bioavailability due to reduced metabolism | | Spontaneous bruising | Supratherapeutic anticoagulation (INR > 4) increases bleeding risk | | Timing (2 weeks) | CYP2C9 inhibition develops over days; warfarin half-life is 36–42 hours, so steady-state elevation occurs by week 2 | ## Management **High-Yield:** When CYP2C9 inhibitors are co-prescribed with warfarin: 1. Monitor INR closely (every 3–5 days initially) 2. Reduce warfarin dose by 20–30% 3. Consider alternative antifungal (e.g., nystatin for oral candidiasis, which is not absorbed and has no interaction) **Clinical Pearl:** Other CYP2C9 inhibitors that interact with warfarin include amiodarone, NSAIDs, sulfonamides, and metronidazole — all require INR monitoring and dose adjustment.