Inhibition of Terfenadine Metabolism

Terfenadine, a nonsedating histamine H I-receptor antagonist, is widely used and is available without prescription in many countries. Terfenadine was initially considered to have a favourable tolerability profile, but there are now several reports indicating an association between use of terfenadine and altered cardiac repolarisation.l I] Overdose, hepatic dysfunction and coadministration of ketoconazole, an inhibitor of cytochrome P450-mediated drug metabolism, were identified as risk factors for terfenadine-associated cardiotoxicity. [2-5] Terfenadine is a prodrug. After oral administration, it undergoes virtually complete first-pass metabolism to 2 metabolites: an active acid metabolite (terfenadine carboxylate) with antihistaminic properties and an inactive dealkylated metabolite (fig. 1 ).[6] Consequently, it is unusual to find detectable plasma concentrations of terfenadine in patients taking the drug at the usual dosage of 120 mg/day. However, it is terfenadine that is responsible for the observed QT prolongation. Therefore, concurrent administration of drugs that inhibit terfenadine metabolism can result in accumulation of terfenadine and induction of potentially lethal ventricular arrhythmias such as torsade de pointes.[7] Considering the widespread use of terfenadine and drugs inhibiting its metabolism (e.g. ketoconazole, itraconazole and erythromycin), it is likely that clinically significant interactions have often been overlooked. Regardless of the efforts of both the Food and Drug Administration of the US and the manufacturer of terfenadine, it appears that current awareness of the potentially harmful drug interactions with terfenadine remains unsatisfactory. Recent data allow a comparative evaluation of the potential of different drugs, especially oral antifungal agents and macrolide antibiotics, to interfere with the metabolism of terfenadine.