Abstract

Background and purpose:The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K+ current (IKr), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a ‘first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here.Experimental approach:hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits.Key results:576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC50, 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 μM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts.Conclusion and implications:The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an ∼15–25% incidence of death.

Highlights

  • In the heart, drug-induced prolongation of the QT interval and the appearance of torsade de pointes (TdPs) are recognized as potential risks associated with the use of a broad range of cardiovascular and non-cardiovascular drugs (Haverkamp et al, 2000; Cubeddu, 2003; Shah, 2004)

  • Our findings showed that an appreciable number of compounds did not affect the human ether-a-go-go-related gene (hERG) channel, but did prolong the action potential duration (APD)

  • An effect was defined as ‘hERG inhibition’ if a compound inhibited hERG current by X20% at a concentration p3 mM, as ‘hERG stimulation’ if a compound activated hERG current X10% at a concentration p3 mM or was considered as ‘no effect’ if a compound was associated with o20% inhibition or o10% activation of hERG current at a concentration p3 mM (n 1⁄4 3–5 per compound and per concentration) or effects appeared only at high concentrations (43 mM)

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Summary

Introduction

Drug-induced prolongation of the QT interval and the appearance of torsade de pointes (TdPs) are recognized as potential risks associated with the use of a broad range of cardiovascular and non-cardiovascular drugs (Haverkamp et al, 2000; Cubeddu, 2003; Shah, 2004). Current established regulatory guidelines (CPMP/986/96, 1997 and International Conference on Harmonisation (ICH) S7B, 2005) recommend the use of preclinical studies to detect drug-induced QT interval prolongation and arrhythmogenic potential. The most common mechanism for drugs that induce prolongation of the QT interval is the inhibition of the rapidly activating delayed rectifier potassium current (IKr) of the cardiac cells. Predicting drug-induced changes in QT interval HR Lu et al. The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K þ current (IKr), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a ‘first line’ test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here. Mallotoxin and NS1643 (hERG current stimulators at 3 mM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts. British Journal of Pharmacology (2008) 154, 1427–1438; doi:10.1038/bjp.2008.191; published online 19 May 2008

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