Tags

Type your tag names separated by a space and hit enter

HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
Circulation. 1996 Aug 15; 94(4):817-23.Circ

Abstract

BACKGROUND

Administration 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 RESULTS

We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value 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.

CONCLUSIONS

Terfenadine 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.

Authors+Show Affiliations

Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109-1998, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8772706

Citation

Roy, M, et al. "HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine." Circulation, vol. 94, no. 4, 1996, pp. 817-23.
Roy M, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation. 1996;94(4):817-23.
Roy, M., Dumaine, R., & Brown, A. M. (1996). HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation, 94(4), 817-23.
Roy M, Dumaine R, Brown AM. HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine. Circulation. 1996 Aug 15;94(4):817-23. PubMed PMID: 8772706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. AU - Roy,M, AU - Dumaine,R, AU - Brown,A M, PY - 1996/8/15/pubmed PY - 1996/8/15/medline PY - 1996/8/15/entrez SP - 817 EP - 23 JF - Circulation JO - Circulation VL - 94 IS - 4 N2 - BACKGROUND: Administration 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 RESULTS: We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value 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. CONCLUSIONS: Terfenadine 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. SN - 0009-7322 UR - https://www.unboundmedicine.com/medline/citation/8772706/HERG_a_primary_human_ventricular_target_of_the_nonsedating_antihistamine_terfenadine_ DB - PRIME DP - Unbound Medicine ER -