Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICHS7B Guidelines

摘要: 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 which are outlined here. Experimental approach: hERG was measured HEK293 cells, stably transfected with channels; action potential duration (APD) arrhythmogenic effects were isolated Purkinje fibres perfused hearts from rabbits. Key results: 576 screened test: 58% identified inhibitors, 39% had no effect 3% classified stimulators. Of 92 tested APD assay: 55.4% these prolonged APD, 28.3% 16.3% shortened APD. 70 without on channels, 54.3% did not affect 25.7% prolonged, while 20% significantly Dofetilide (hERG inhibitor; IC50, 29 nM) elicited early after-depolarizations and/or torsade de pointes (TdP) hearts. Mallotoxin NS1643 stimulators at 3 μM), levcromakalim nicorandil (no current), all QT, ventricular fibrillation (VF) hearts. Conclusion implications: The assay alone adequately identify drugs prolongation. It is also important to detect drug-induced shortening, this associated risk tachycardia VF, latter being invariably fatal, whereas TdP has an ∼15–25% incidence death. British Journal Pharmacology (2008) 154, 1427–1438; doi:10.1038/bjp.2008.191; published online 19 May 2008