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The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia.
Br J Pharmacol. 2002 Nov; 137(6):892-900.BJ

Abstract

1. The human HERG gene encodes the cardiac repolarizing K(+) current I(Kr) and is genetically inactivated in inherited long QT syndrome 2 (LQTS2). The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity. 2. In the present study the ability of fexofenadine to block the K897T HERG channel variant was investigated. The underlying single nucleotide polymorphism (SNP) A2960C was identified in a patient reported to develop fexofenadine-associated LQTS. 3. K897T HERG channels produced wild-type-like currents in Xenopus oocytes. Even at a concentration of 100 micro M, fexofenadine did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and K897T HERG with the ss-subunit MiRP1, slightly changed current kinetics but did not change sensitivity to terfenadine and fexofenadine. 4. Western blot analysis and immunostaining of transiently transfected COS-7 cells demonstrated that overall expression level, glycosylation pattern and subcellular localization of K897T HERG is indistinguishable from wild-type HERG protein, and not altered in the presence of 1 micro M fexofenadine. 5. We provide the first functional characterization of the K897T HERG variant. We demonstrated that K897T HERG is similar to wild-type HERG, and is insensitive to fexofenadine. Although the polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG by these kinases is not altered. 6. Our results strongly indicate that QT lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are not due to the K897T exchange or to an inhibitory effect of fexofenadine on cardiac I(Kr) currents. British Journal of

Authors+Show Affiliations

Aventis Pharma Deutschland GmbH, Cardiovascular Diseases, 65926 Frankfurt am Main, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

12411421

Citation

Scherer, Constanze R., et al. "The Antihistamine Fexofenadine Does Not Affect I(Kr) Currents in a Case Report of Drug-induced Cardiac Arrhythmia." British Journal of Pharmacology, vol. 137, no. 6, 2002, pp. 892-900.
Scherer CR, Lerche C, Decher N, et al. The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol. 2002;137(6):892-900.
Scherer, C. R., Lerche, C., Decher, N., Dennis, A. T., Maier, P., Ficker, E., Busch, A. E., Wollnik, B., & Steinmeyer, K. (2002). The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. British Journal of Pharmacology, 137(6), 892-900.
Scherer CR, et al. The Antihistamine Fexofenadine Does Not Affect I(Kr) Currents in a Case Report of Drug-induced Cardiac Arrhythmia. Br J Pharmacol. 2002;137(6):892-900. PubMed PMID: 12411421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. AU - Scherer,Constanze R, AU - Lerche,Christian, AU - Decher,Niels, AU - Dennis,Adrienne T, AU - Maier,Patrick, AU - Ficker,Eckhard, AU - Busch,Andreas E, AU - Wollnik,Bernd, AU - Steinmeyer,Klaus, PY - 2002/11/2/pubmed PY - 2003/4/9/medline PY - 2002/11/2/entrez SP - 892 EP - 900 JF - British journal of pharmacology JO - Br J Pharmacol VL - 137 IS - 6 N2 - 1. The human HERG gene encodes the cardiac repolarizing K(+) current I(Kr) and is genetically inactivated in inherited long QT syndrome 2 (LQTS2). The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity. 2. In the present study the ability of fexofenadine to block the K897T HERG channel variant was investigated. The underlying single nucleotide polymorphism (SNP) A2960C was identified in a patient reported to develop fexofenadine-associated LQTS. 3. K897T HERG channels produced wild-type-like currents in Xenopus oocytes. Even at a concentration of 100 micro M, fexofenadine did not inhibit wild-type or K897T HERG channels. Coexpression of wild-type and K897T HERG with the ss-subunit MiRP1, slightly changed current kinetics but did not change sensitivity to terfenadine and fexofenadine. 4. Western blot analysis and immunostaining of transiently transfected COS-7 cells demonstrated that overall expression level, glycosylation pattern and subcellular localization of K897T HERG is indistinguishable from wild-type HERG protein, and not altered in the presence of 1 micro M fexofenadine. 5. We provide the first functional characterization of the K897T HERG variant. We demonstrated that K897T HERG is similar to wild-type HERG, and is insensitive to fexofenadine. Although the polymorphism changes PKA and PKC phosphorylation sites, regulation of K897T HERG by these kinases is not altered. 6. Our results strongly indicate that QT lengthening and cardiac arrhythmia in the reported case of drug-induced LQT are not due to the K897T exchange or to an inhibitory effect of fexofenadine on cardiac I(Kr) currents. British Journal of SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/12411421/The_antihistamine_fexofenadine_does_not_affect_I_Kr__currents_in_a_case_report_of_drug_induced_cardiac_arrhythmia_ L2 - https://doi.org/10.1038/sj.bjp.0704873 DB - PRIME DP - Unbound Medicine ER -