A patient previously stabilised on terfenadine is started on ketoconazole for tinea corporis and develops marked QT prolongation with episodes of torsades de pointes. The interaction occurred because terfenadine:

• A Competes with ketoconazole for renal tubular secretion
• B Requires CYP3A4 metabolism, which ketoconazole potently inhibits, allowing accumulation of the parent drug that blocks cardiac potassium channels ✓
• C Displaces ketoconazole from plasma proteins, raising free ketoconazole levels
• D Induces CYP3A4, increasing formation of a cardiotoxic metabolite

Explanation

Terfenadine is a prodrug converted almost entirely by intestinal and hepatic CYP3A4 to fexofenadine, its active non-cardiotoxic metabolite. Strong CYP3A4 inhibitors like ketoconazole and erythromycin block this conversion, so parent terfenadine accumulates and blocks delayed rectifier potassium channels (hERG), prolonging QT and triggering torsades. This interaction led to terfenadine's withdrawal and replacement by fexofenadine itself. Protein displacement and induction are irrelevant here.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.