DOI: 10.1161/01.cir.94.4.817. HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine

HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine

10.1161/01.cir.94.4.817

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation (276)

Abstract

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.

Bibliography

Roy, M.-L., Dumaine, R., & Brown, A. M. (1996). HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine. Circulation, 94(4), 817â823.

Authors 3

Mary-Louise Roy (first)
Robert Dumaine (additional)
Arthur M. Brown (additional)

References 39 Referenced 249

1992 National Prescription Audit. IMS America Ltd Plymouth Meeting Pa 1992.
10.1001/jama.1993.03500120051025
Davies AJ, Harinda V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. Br Med J. 1989;298:325. Abstract. / Br Med J (1989)
10.1001/jama.1990.03450210088038
10.1093/oxfordjournals.eurheartj.a060277
Zechnich AD, Hedges JR, Eiselt-Proteau D, Haxby D. Possible interactions with terfenadine or astemizole. West J Med. 1994;160:321-325. / West J Med (1994)
Jurima-Romet M, Crawford K, Cyr T, Inaba T. Terfenadine metabolism in human liver: in vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab Dis. 1994;22:849-857. (10.1016/S0090-9556(25)08427-2) / Drug Metab Dis (1994)
Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF III, Guinosso PJ Jr, Lynch JJ Jr. Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circ Res. 1995;73:110-119. / Circ Res (1995)
10.1161/01.RES.74.6.1071
10.1097/00005344-199205000-00022
Sanguinetti MC Jurkiewicz NK. Delayed rectifier potassium channels of cardiac muscle. In: Spooner PM Brown AM eds. Ion Channels in the Cardiovascular System: Function and Dysfunction. Armork NY: Futura Publishing Co Inc; 1994;121-143.
10.1113/jphysiol.1969.sp008689
10.1085/jgp.96.1.195
10.1085/jgp.96.4.835
10.1007/BF00581319
10.1161/res.73.6.8222078
10.1161/res.73.1.8508531
10.1001/jama.1993.03500120070028
Crumb WJ, Wible BA, Arnold DJ, Payne JP, Brown AM. Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity. Mol Pharmacol. 1995;47:181-190. (10.1016/S0026-895X(25)08517-7) / Mol Pharmacol (1995)
10.1161/circ.91.8.2220
10.1073/pnas.91.8.3438
10.1016/0092-8674(95)90363-1
10.1126/science.7604285
10.1016/0092-8674(95)90358-5
10.1126/science.8171340
Rampe D, Wible BA, Brown AM, Dage RC. Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart. J Pharmacol Exp Ther. 1993;44:1240-1245. / J Pharmacol Exp Ther (1993)
10.1016/S0006-3495(95)80053-6
10.1111/j.1540-8167.1993.tb01214.x
10.1161/01.RES.78.3.499
10.1007/BF01258466
Amos GJ Wettwer E Li Q Himmel HM Ravens U. Differences in outward currents of human atrial and ventricular myocytes. Circulation. 1994;4(suppl I):I-581. Abstract.
10.1096/fasebj.5.3.2001794
10.1126/science.3194754
10.1016/0006-291X(89)91577-5
10.1073/pnas.87.8.2975
10.1161/res.77.1.140
10.1016/0002-9149(92)91306-O
10.1097/00005344-199309000-00014
10.2165/00003495-198529010-00002

Dates

Type	When
Created	13 years, 2 months ago (June 11, 2012, 8:34 p.m.)
Deposited	4 months, 4 weeks ago (March 30, 2025, 3:52 p.m.)
Indexed	2 days, 3 hours ago (Aug. 27, 2025, 12:27 p.m.)
Issued	29 years ago (Aug. 15, 1996)
Published	29 years ago (Aug. 15, 1996)
Published Print	29 years ago (Aug. 15, 1996)

Funders 0

None

BibTeX

@article{Roy_1996, title={HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine}, volume={94}, ISSN={1524-4539}, url={http://dx.doi.org/10.1161/01.cir.94.4.817}, DOI={10.1161/01.cir.94.4.817}, number={4}, journal={Circulation}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Roy, Mary-Louise and Dumaine, Robert and Brown, Arthur M.}, year={1996}, month=aug, pages={817–823} }

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