CYP2J2 inhibition: the arcane mechanism of dronedarone‐induced proarrhythmia

Abstract

BackgroundLike other Class III antiarrhythmic, dronedarone and amiodarone are potent human Ether‐à‐go‐go‐Related Gene (hERG) channel inhibitors.1–2 Although structurally and pharmacologically similar, dronedarone is known to worsen cardiac proarrhythmia3 and increase mortality in patients with permanent atrial fibrillation4 while amiodarone does not. Previously we demonstrated dronedarone is a more potent inhibitor of recombinant human cytochrome P4502J2 (CYP2J2)4 compared to amiodarone and yields negative perturbation of eicosatrienoic acid homeostasis5.ObjectivesWe aimed to investigate and compare the in vitro proarrhythmic potential of dronedarone and amiodarone and CYP2J2 inhibition in a cellular model.MethodsWe first measured the expression of CYP2J2 in human induced pluripotent stem cell derived cardiomyocytes (hiPSC‐CMs) using quantitative PCR. The extent of CYP2J2 inhibition in hiPSC‐CMs was measured using astemizole as a probe substrate. The electrophysiological changes in terms of field potential duration (FPD) and beat rate variability (BRV) were measured using multielectrode array.ResultsCYP2J2 is abundantly expressed in hiPSC‐CMs. Unlike amiodarone, dronedarone potently inhibited CYP2J2 activity (97%) at 1 μM. Both dronedarone and amiodarone yielded concentration‐dependent increase in FPD. Dronedarone showed 17‐fold and 2‐fold higher BRV compared to control and amiodarone at unbound plasma drug concentrations. Higher extent of CYP2J2 inhibition correlates with higher BRV.ConclusionDronedarone‐induced BRV corroborates its clinical proarrhythmia. For the first time, our study illuminates the currently arcane contribution of CYP2J2 inhibition to drug‐induced proarrhythmia.Support or Funding InformationSingapore Ministry of Education Tier 1 Funding (R‐148‐000‐193‐112) provided to Eric Chun Yong Chan.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.