A 65-year-old woman with atrial fibrillation presents to her cardiologist for rate control. She has been stable on warfarin (target INR 2-3) for 6 months for stroke prevention. Her baseline INR was 2.4 one month ago. The cardiologist initiates diltiazem 120 mg daily for rate control due to recurrent palpitations and a resting heart rate of 108 bpm. Five days later, the patient returns for routine INR monitoring. Laboratory results show INR 4.8 (PT 42 seconds, control 12 seconds). The patient denies any signs of bleeding, and her vital signs are stable. Which of the following best explains the elevated INR in this patient?

1. A)Diltiazem competitively inhibits CYP2C9, the primary isoenzyme responsible for S-warfarin metabolismGABARITO
2. B)Diltiazem induces hepatic metabolism of warfarin through upregulation of CYP3A4
3. C)Diltiazem displaces warfarin from plasma protein binding, increasing the free fraction of warfarin
4. D)Diltiazem inhibits vitamin K epoxide reductase, potentiating warfarin's anticoagulant effect
5. E)Diltiazem reduces intestinal absorption of warfarin, leading to compensatory increased metabolism