BackgroundAdministration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K+current (IKur) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go–related gene that expresses a delayed rectifier current (IKr) in human ventricle and produces hereditary long QT syndrome when defective.Methods and ResultsWe therefore heterologously expressed Kv1.5 and HERG inXenopusoocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparentKdvalues for HERG and Kv1.5 currents were 350 nmol/L and 2.7 μmol/L, respectively. TheseKdvalues compare well with values reported for terfenadine block of IKrand IKurcurrents in human atrial myocytes. TheKdvalue for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range.ConclusionsTerfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.