An ambulatory care pharmacist reviews the medication profile of a 62-year-old woman with a mechanical aortic valve. She is currently taking a stable dose of warfarin, and her international normalized ratio (INR) has been consistently in the therapeutic range of 2.5 to 3.5. The patient was recently diagnosed with vaginal candidiasis and was prescribed a short course of oral fluconazole by her primary care provider. Four days later, she presents to the urgent care clinic complaining of significant gingival bleeding and large ecchymoses on her extremities. Laboratory testing reveals an INR of 7.2. Which of the following pharmacokinetic mechanisms is the most likely cause of this patient's elevated INR and subsequent bleeding?
- Inhibition of cytochrome P450-mediated metabolismAnswer
- BDisplacement of the anticoagulant from plasma albumin
- CInduction of hepatic cytochrome P450 enzymes
- DDecreased renal clearance of active drug metabolites
- EEradication of intestinal flora leading to decreased vitamin K synthesis
Answer
Inhibition of cytochrome P450-mediated metabolism
The correct answer correctly identifies that fluconazole causes a classic pharmacokinetic drug-drug interaction through the inhibition of cytochrome P450 enzymes. Specifically, it inhibits CYP2C9, the primary metabolic pathway for the highly active S-enantiomer of warfarin. This inhibition abruptly halts the hepatic clearance of warfarin, causing plasma levels to rise rapidly and extending the anticoagulant effect, which manifests as an unexpectedly high INR and spontaneous bleeding.
Step-by-Step Solution
Key Concept
Fluconazole strongly inhibits CYP2C9, which is the primary enzyme responsible for metabolizing the more potent S-enantiomer of warfarin, leading to decreased clearance, drug accumulation, and an increased risk of bleeding.