A patient on fluconazole for oesophageal candidiasis is noted to have a significantly elevated INR while also taking warfarin. The mechanism of this interaction is:

• A Fluconazole induces CYP2C9 and CYP3A4, increasing warfarin metabolism
• B Fluconazole displaces warfarin from plasma albumin binding sites, increasing free warfarin
• C Fluconazole inhibits vitamin K absorption from the gut, enhancing warfarin effect
• D Fluconazole inhibits CYP2C9 (the major enzyme metabolising S-warfarin), increasing warfarin plasma levels and anticoagulant effect ✓

Explanation

Fluconazole is a potent inhibitor of CYP2C9 and also inhibits CYP3A4. S-warfarin (the more pharmacologically active enantiomer) is metabolised predominantly by CYP2C9. Fluconazole inhibition of CYP2C9 substantially increases S-warfarin plasma levels, prolonging the INR by 50–100% or more. R-warfarin, metabolised by CYP3A4 and CYP1A2, is less affected but also increases with fluconazole. This interaction requires warfarin dose reduction (typically by 25–50%) and close INR monitoring. All triazole antifungals (itraconazole, voriconazole, posaconazole) have similar but varying degrees of CYP inhibition.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.