A common antitussive drug, clobutinol, precipitates the long QT syndrome 2

Chloé Bellocq, Ronald Wilders, Jean-Jacques Schott, Bénédicte Louérat-Oriou, Pierre Boisseau, Hervé Le Marec, Denis Escande, Isabelle Baró

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QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K(+) current with a half-maximum block concentration of 2.9 microM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K(+) current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a approximately -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes"
Original languageEnglish
Pages (from-to)1093-1102
JournalMolecular Pharmacology
Issue number5
Publication statusPublished - 2004

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