Abstract
Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans, however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking. The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current (IKr) encoded by HERG (the human ether-a-go-go-related gene) at drug concentrations, temperature and ionic conditions mimicking those occurring in human subjects. Potassium currents in HEK 293 cells stably transfected with HERG were recorded using a whole cell voltage clamp method. Exposure of cells to erythromycin reduced the HERG encoded potassium current in a concentration dependent manner with an IC50 of 38.9 ± 1.2 μM and Hill Slope factor of 0.4 ± 0.1. Clarithromycin produced a similar concentration-dependent block with an IC50 of 45.7 ± 1.1 μM and Hill Slope factor of 1.0 ± 0.1. Erythromycin (25–250 μM) and clarithromycin (5 or 25 μM) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol. The results of this study document that both erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations.
Similar content being viewed by others
References
Kundu S, Williams SR, Nordt SP, Clark RF: Clarithromycin-induced ventricular tachycardia. Ann Emerg Med 30: 542-544, 1997
McComb JM, Campbell NPS, Cleland J: Recurrent ventricular tachycardia associated with QT prolongation after mitral valve replacement and its association with intravenous administration of erythromycin. Am J Cardiol 54: 922-923, 1984
Nattel S, Ranger S, Talajic M, Lemery R, Roy D: Erythromycin-induced long QT syndrome: Concordance with quinidine and underlying cellular electrophysiologic mechanism. Am J Med 89: 235-238, 1990
Schoenenberger RA, Haefeli WE, Weiss P, Ritz RF: Association of intravenous erythromycin and potentially fatal ventricular tachycardia with Q-T prolongation (torsade de pointes). Br Med J 300: 1376-1377, 1990
Katapadi K, Kostandy G, Katapadi M, Hussain KMA, Schifter D: A review of erythromycin-induced malignant tachyarrhythmia — torsades de pointes. Angiology 48: 821-826, 1997
Lee KL, Jim MH, Tang SC, Tai YT: QT prolongation and torsade de pointes associated with clarithromycin. Am J Med 104: 395-396, 1998
Kamochi H, Nii T, Eguchi K, Mori T, Yamamoto A, Shimoda K, Ibaraki K: Clarithromycin associated with torsade de pointes. Japanese Circ J 63: 421-422, 1999
Austin KL, Mather LE, Philpot CR, McDonald PJ: Intersubject and dose-related variability after intravenous administration of erythromycin. Br J Clin Med 10: 273-279, 1980
Daleau P, Lessard E, Groleau, MF, Turgeon J: Erythromycin blocks the rapid component of the delayed rectifier potassium current and lengthens repolarization of guinea pig ventricular myocytes. Circulation 91: 3010-3016, 1995
Antzelevitch C, Sun Z-Q, Zhang Z-Q, Yan G-X: Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol 28: 1836-1848, 1996
Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SAN: Mirp1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmias. Cell 97: 175-187, 1999
Biaxin. In: Physicians Desk Reference, 54th edn. Medical Economics Company, Inc. Montvale, NJ, p 409, 2000
Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT: Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 74: 230-241, 1998
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ: Improved patch clamp techniques for high-resolution current recording from cells and cells-free membrane patches. Pflügers Arch 391: 85-100, 1981
Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL Jr, Goldstein SA: A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA 97: 10613-10618, 2000
Jo S-H, Youm JB, Lee CO, Earm YE, Ho WK: Blockade of the HERG human cardiac K+ channel by the antidepressant drug amitriptyline. Br J Pharmacol 129: 1474-1480, 2000
Ferreira S, Crumb WJ Jr, Carlton CG, Clarkson CW: Effects of cocaine and its major metabolites on the HERG-encoded potassium channel. J Pharmacol Exper Ther 299: 220-226, 2001
Yeola SW, Rich TC, Uebele VN, Tamkun MM, Snyders DJ: Molecular analysis of a binding site for quinidine in a human cardiac delayed rectifier K channel. Role of S6 in antiarrhythmic drug binding. Circ Res 78: 1105-1114, 1996
Nilsen OG: Comparative pharmacokinetics of macrolides. J Antimicrob Chemother 20(B): 81-88, 1987
Brandriss MW, Richardson WS, Barold SS: Erythromycin-induced QT prolongation and polymorphic ventricular tachycardia (torsades de pointes): Case report and review. Clin Infect Dis 18: 995-998, 1994
Dette GA, Knothe H, Herrmann G: Erythromycin binding to human serum. Biochem Pharmacol 31: 1081-1087, 1982
Davey PG: The pharmacokinetics of clarithromycin and its 14-OH metabolite. J Hosp Infect 19(suppl A): 29-37, 1991
Yoshida H, Furata T: Tissue penetration properties of macrolide antibiotics — comparative tissue distribution of erythromycin-stearate, clarithromycin, roxithromycin and azithromycin in rats. Japanese J Antibiot 52: 497-503, 1999
Dette GA, Knothe H, Kellner HM: Whole body tissue distribution of [14C]-erythromycin in the guinea pig. Arzneimittelforschung 37: 524-527, 1987
Oberg KC, Bauman JL: QT interval prolongation and torsade dep pointes due to erythromycin lactobionate. Pharmacotherapy 15: 687-692, 1995
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stanat, S.J., Carlton, C.G., Crumb, W.J. et al. Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel. Mol Cell Biochem 254, 1–7 (2003). https://doi.org/10.1023/A:1027309703313
Issue Date:
DOI: https://doi.org/10.1023/A:1027309703313