A patient taking terfenadine develops prolongation of the QT interval and torsades de pointes after starting a course of ketoconazole for tinea corporis. The pharmacokinetic basis of this interaction is:

• A Ketoconazole inhibits CYP3A4, causing accumulation of unmetabolised parent terfenadine ✓
• B Ketoconazole induces CYP3A4, increasing formation of a cardiotoxic metabolite
• C Ketoconazole displaces terfenadine from plasma protein binding sites
• D Ketoconazole inhibits P-glycoprotein, increasing brain penetration of terfenadine

Explanation

Terfenadine is normally almost completely converted by intestinal and hepatic CYP3B4 to fexofenadine, its active but non-cardiotoxic carboxylate metabolite. Ketoconazole and erythromycin inhibit this metabolism, allowing the parent compound to accumulate and block cardiac hERG potassium channels, producing QT prolongation and torsades. This interaction led to terfenadine withdrawal and replacement by fexofenadine, which is safe with CYP3B4 inhibitors.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.