Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart

D Rampe, B Wible, AM Brown and RC Dage

Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.

Use of the nonsedating antihistamine terfenadine has been associated with altered cardiac repolarization in certain clinical settings. For this reason we examined the effects of terfenadine, and its metabolites, on a rapidly activating delayed rectifier K+ channel (fHK) cloned from human heart. fHK was stably expressed in human embryonic kidney cells, and both whole-cell currents and currents from excised inside-out patches were recorded. Terfenadine (3 microM) blocked whole- cell fHK current by 72 +/- 6%. In inside-out patches, terfenadine applied to the cytoplasmic surface blocked fHK with an IC50 value of 367 nM. The main effect of terfenadine was to enhance the rate of inactivation of fHK current and thereby reduce the current at the end of a prolonged voltage-clamp pulse. The blockade displayed a weak voltage dependence, increasing at more positive potentials. The mechanism of action of terfenadine is therefore consistent with blockade of open channels. In contrast, the metabolites of terfenadine were weakly active on fHK. IC50 values for all of the metabolites tested ranged from 27-fold to 583-fold higher than that obtained for terfenadine. It is concluded that terfenadine, but not its metabolites, blocks at least one type of human cardiac K+ channel at clinically relevant concentrations and that this activity may underlie the cardiac arrhythmias that have been associated with the use of this drug.

Volume 44, Issue 6, pp. 1240-1245, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				H. Choe, Y.-K. Lee, Y.-T. Lee, H. Choe, S.-H. Ko, C.-U. Joo, M.-H. Kim, G.-S. Kim, J.-S. Eun, J.-H. Kim, et al. Papaverine Blocks hKv1.5 Channel Current and Human Atrial Ultrarapid Delayed Rectifier K+ Currents J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 706 - 712. [Abstract] [Full Text] [PDF]

				A.E. Lacerda, J. Kramer, K.-Z. Shen, D. Thomas, and A.M. Brown Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K23 - K30. [Abstract] [PDF]

				W. J. Crumb Jr. Loratadine Blockade of K+ Channels in Human Heart: Comparison with Terfenadine under Physiological Conditions J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 261 - 264. [Abstract] [Full Text]

				M. Khalifa, B. Drolet, P. Daleau, C. Lefez, M. Gilbert, S. Plante, G. E. O'Hara, O. Gleeton, B. A. Hamelin, and J. Turgeon Block of Potassium Currents in Guinea Pig Ventricular Myocytes and Lengthening of Cardiac Repolarization in Man by the Histamine H1 Receptor Antagonist Diphenhydramine J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 858 - 865. [Abstract] [Full Text]

				S. Hu, S. Wang, J. Gibson, and T. A. Gilbertson Inhibition of Delayed Rectifier K+ Channels by Dexfenfluramine (Redux) J. Pharmacol. Exp. Ther., November 1, 1998; 287(2): 480 - 486. [Abstract] [Full Text]

				M. Nishio, Y. Habuchi, H. Tanaka, J. Morikawa, T. Yamamoto, and K. Kashima Blockage by Terfenadine of the Adenosine Triphosphate (ATP)-Sensitive K+ Current in Rabbit Ventricular Myocytes J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 293 - 300. [Abstract] [Full Text]

				R. Dumaine, M.-L. Roy, and A. M. Brown Blockade of HERG and Kv1.5 by Ketoconazole J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 727 - 735. [Abstract] [Full Text]

				P. D. West, D. K. Martin, J. A. Bursill, K. R. Wyse, and T. J. Campbell Comparative Study of the Effects of Erythromycin and Roxithromycin on Action Potential Duration and Potassium Currents in Canine Purkinje Fibers and Rabbit Myocardium Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(1): 29 - 36. [Abstract] [PDF]

				L. Franqueza, M. Longobardo, J. Vicente, E. Delpon, M. M. Tamkun, J. Tamargo, D. J. Snyders, and C. Valenzuela Molecular Determinants of Stereoselective Bupivacaine Block of hKv1.5 Channels Circ. Res., December 19, 1997; 81(6): 1053 - 1064. [Abstract] [Full Text]

				S. Liu, R. B. Melchert, and R. H. Kennedy Inhibition of L-Type Ca2+ Channel Current in Rat Ventricular Myocytes by Terfenadine Circ. Res., August 19, 1997; 81(2): 202 - 210. [Abstract] [Full Text]

				A. E. Lacerda, M.-L. Roy, E. W. Lewis, and D. Rampe Interactions of the Nonsedating Antihistamine Loratadine with a Kv1.5-Type Potassium Channel Cloned from Human Heart Mol. Pharmacol., August 1, 1997; 52(2): 314 - 322. [Abstract] [Full Text]

				E. Delpon, C. Valenzuela, P. Gay, L. Franqueza, D. J Snyders, and J. Tamargo Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels Cardiovasc Res, August 1, 1997; 35(2): 341 - 350. [Abstract] [Full Text] [PDF]

				C. M. Ko, I. Ducic, J. Fan, Y. M. Shuba, and M. Morad Suppression of Mammalian K+ Channel Family by Ebastine J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 233 - 244. [Abstract] [Full Text]

				S. W. Yeola, T. C. Rich, V. N. Uebele, M. M. Tamkun, and D. J. Snyders 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., June 1, 1996; 78(6): 1105 - 1114. [Abstract] [Full Text]

				D. J. Snyders and S. W. Yeola Determinants of Antiarrhythmic Drug Action : Electrostatic and Hydrophobic Components of Block of the Human Cardiac hKv1.5 Channel Circ. Res., September 1, 1995; 77(3): 575 - 583. [Abstract] [Full Text]

				P. Daleau, E. Lessard, M.-F. Groleau, and J. Turgeon Erythromycin Blocks the Rapid Component of the Delayed Rectifier Potassium Current and Lengthens Repolarization of Guinea Pig Ventricular Myocytes Circulation, June 15, 1995; 91(12): 3010 - 3016. [Abstract] [Full Text]

				C. I. Berul and M. Morad Regulation of Potassium Channels by Nonsedating Antihistamines Circulation, April 15, 1995; 91(8): 2220 - 2225. [Abstract] [Full Text]

				E. S. Levitan, R. Gealy, J. S. Trimmer, and K. Takimoto Membrane Depolarization Inhibits Kv1.5 Voltage-gated K[IMAGE] Channel Gene Transcription and Protein Expression in Pituitary Cells J. Biol. Chem., March 17, 1995; 270(11): 6036 - 6041. [Abstract] [Full Text] [PDF]

				J. J. Salata, N. K. Jurkiewicz, A. A. Wallace, R. F. Stupienski III, P. J. Guinosso Jr, and J. J. Lynch Jr Cardiac Electrophysiological Actions of the Histamine H1-Receptor Antagonists Astemizole and Terfenadine Compared With Chlorpheniramine and Pyrilamine Circ. Res., January 1, 1995; 76(1): 110 - 119. [Abstract] [Full Text]

				F. E. R. Simons and K. J. Simons The Pharmacology and Use of H1-Receptor-Antagonist Drugs N. Engl. J. Med., June 9, 1994; 330(23): 1663 - 1670. [Full Text]