Terfenadine was withdrawn from the market after reports of fatal ventricular arrhythmia when co-prescribed with ketoconazole or erythromycin. The pharmacokinetic basis of this interaction is:
- A Ketoconazole displaces terfenadine from plasma protein binding, raising free drug levels
- B Both agents inhibit CYP3A4, preventing conversion of terfenadine to fexofenadine and allowing accumulation of the parent drug, which blocks cardiac potassium channels ✓
- C Erythromycin induces CYP3A4, accelerating formation of a cardiotoxic metabolite
- D The combination saturates P-glycoprotein efflux at the blood-brain barrier
Correct answer: B. Both agents inhibit CYP3A4, preventing conversion of terfenadine to fexofenadine and allowing accumulation of the parent drug, which blocks cardiac potassium channels
Explanation
Terfenadine is normally almost completely metabolised by intestinal and hepatic CYP3A4 to fexofenadine, its active but non-cardiotoxic carboxylate metabolite. Strong CYP3A4 inhibitors raise parent terfenadine levels, which block hERG potassium channels and cause QT prolongation with torsades de pointes. This led to terfenadine's withdrawal and replacement by fexofenadine, which is given directly, is not CYP3A4 dependent, and does not prolong QT.
Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.
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