Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts  

作　　者：Aneesh V.Karkhanis Gopalakrishnan Venkatesan Ryuichi Kambayashi Jacqueline Wen Hui Leow Marcus Qingrui Han Hiroko Izumi-Nakaseko Ai Goto Jeremy Kah Sheng Pang Boon Seng Soh Pipin Kojodjojo Atsushi Sugiyama Eric Chun Yong Chan 

机构地区：[1]Department of Pharmacy,Faculty of Science,National University of Singapore,Singapore 117543,Singapore [2]Department of Pharmacology,Faculty of Medicine,Toho University,Tokyo 143-8540,Japan [3]Institute of Molecular and Cell Biology,Agency for Science,Technology and Research,Singapore 138673,Singapore [4]Department of Biological Sciences,Faculty of Science,National University of Singapore,Singapore 117558,Singapore [5]Department of Medicine,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 119228,Singapore

出　　处：《Acta Pharmaceutica Sinica B》2022年第10期3905-3923,共19页药学学报（英文版）

基　　金：supported by the National University Heart Centre Singapore (NUHCS) Cardiovascular Research Institute (CVRI)Core Fund [Grant NUHSRO/2019/082/Core];SCEPTRE CG Seed Grant [Grant NMRC/CG/M008/2017, Singapore];Singapore Ministry of Education Tier 1 Academic Research Funding [Grant R-148-000-193-112];the National University of Singapore, Department of Pharmacy, Final Year Project Funding [Grant C148-000-003-001] provided to Eric Chun Yong Chan;from Japan Society for the Promotion of Science (JSPS) KAKENHI [grant number 20K16136] provided to Ryuichi Kambayashi

摘　　要：Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood mechanisms.We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment.In this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs.We first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro.Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration.Next,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic phenotype.In contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity.Importantly,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk.Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.

关 键 词：Arachidonic acid Atrial fibrillation CYP2J2 Drug-induced proarrhythmia Epoxyeicosatrienoic acids Mechanism-based inactivation DRONEDARONE 

分 类 号：R965[医药卫生—药理学]