A step towards characterisation of electrophysiological profile of torsadogenic drugs

作者：Champeroux Pascal^*; Ouille Aude; Martel Eric; Fowler John Sinclair Lawrence; Maurin Anne; Richard Serge; Le Guennec Jean Yves

来源：Journal of Pharmacological and Toxicological Methods, 2011, 63(3): 269-278.

DOI：10.1016/j.vascn.2011.01.001

• Electrocardiogram
• Patch-clamp
• Purkinje fibres
• QT prolongation
• Safety pharmacology
• Telemetry

Introduction: In a previous study, two electrophysiological patterns for torsadogenic drugs were characterised in the model of isolated canine Purkinje fibres from their respective effects on action potential. This study was designed to elucidate the possible mechanisms underlying these two electrophysiological profiles. Methods: Effects of representative torsadogenic agents and non torsadogenic drugs on IK(r), IK(s), IK(1), I(Na) and I(CaL) were studied in transfected HEK 293 cells using the path-clamp method as well as in conscious beagle dogs and cynomolgus monkeys by telemetry. Results: Patch-clamp studies confirmed that torsadogenic molecules could be discriminated into at least two subgroups. The first subgroup can be defined as apparently pure blockers. The second subgroup can be defined as I(Kr) blockers with ancillary properties on sodium and/or calcium channels which counterbalance the I(Kr) prolongation component. This discrimination is transposable to the telemetered cynomolgus monkey model in terms of QT prolongation but not to the telemetered beagle dog model. This latter inter-species difference could be related to the sympathetic/parasympathetic balance and could involve reserve repolarisation dependent mechanisms. Discussion: The confirmation that torsadogenic drugs might have at least two different electrophysiological profiles should be taken into consideration in preclinical safety pharmacology studies because it increases the value of the cynomolgus monkey model in two particular situations: firstly when an NCE causes sympathetic activation and secondly, when an NCE exhibits a pure blocker pattern independently of its potency to block HERG channels.

• 出版日期2011-6