A step towards characterisation of electrophysiological profile of torsadogenic drugs

IntroductionIn 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.MethodsEffects of representative torsadogenic agents and non torsadogenic drugs on IKr, IKs, IK1, INa and ICaL were studied in transfected HEK 293 cells using the path-clamp method as well as in conscious beagle dogs and cynomolgus monkeys by telemetry.ResultsPatch-clamp studies confirmed that torsadogenic molecules could be discriminated into at least two subgroups. The first subgroup can be defined as apparently pure IKr blockers. The second subgroup can be defined as IKr blockers with ancillary properties on sodium and/or calcium channels which counterbalance the IKr 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.DiscussionThe 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 IKr blocker pattern independently of its potency to block HERG channels.