A 45-year-old man with a history of atrial fibrillation presents with a 3-week productive cough, night sweats, and 8-lb weight loss. Chest X-ray demonstrates a left upper lobe cavitary infiltrate, and acid-fast bacilli are seen on sputum smear microscopy. He is started on standard four-drug TB therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. His current medications include warfarin, which he has been taking for 2 years with a stable INR of 3.0–3.5 for stroke prevention. Vital signs show temperature 38.2°C, heart rate 88 bpm, BP 128/82 mmHg. One week after initiating TB therapy, his INR is measured at 1.6, well below the target range. His warfarin dose has not been changed. He reports good adherence to both medications and denies any recent dietary changes, alcohol use, or over-the-counter medications. Which of the following TB medications is responsible for this change in INR?

1. A)Isoniazid, which competitively inhibits warfarin metabolism via CYP2C9
2. B)Pyrazinamide, which induces hepatic glucuronidation of warfarin metabolites
3. C)Rifampin, which potently induces multiple cytochrome P450 enzymes including CYP2C9GABARITO
4. D)Ethambutol, which inhibits warfarin protein binding and increases free warfarin levels
5. E)A synergistic interaction between isoniazid and rifampin that inhibits warfarin clearance