PMID- 36213535
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221011
IS  - 2211-3835 (Print)
IS  - 2211-3843 (Electronic)
IS  - 2211-3835 (Linking)
VI  - 12
IP  - 10
DP  - 2022 Oct
TI  - Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity 
      and mitigates its cardiac adverse effects in canine arrhythmic hearts.
PG  - 3905-3923
LID - 10.1016/j.apsb.2022.03.008 [doi]
AB  - 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.
CI  - (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, 
      Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
FAU - Karkhanis, Aneesh V
AU  - Karkhanis AV
AD  - Department of Pharmacy, Faculty of Science, National University of Singapore, 
      Singapore 117543, Singapore.
FAU - Venkatesan, Gopalakrishnan
AU  - Venkatesan G
AD  - Department of Pharmacy, Faculty of Science, National University of Singapore, 
      Singapore 117543, Singapore.
FAU - Kambayashi, Ryuichi
AU  - Kambayashi R
AD  - Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo 143-8540, 
      Japan.
FAU - Leow, Jacqueline Wen Hui
AU  - Leow JWH
AD  - Department of Pharmacy, Faculty of Science, National University of Singapore, 
      Singapore 117543, Singapore.
FAU - Han, Marcus Qingrui
AU  - Han MQ
AD  - Department of Pharmacy, Faculty of Science, National University of Singapore, 
      Singapore 117543, Singapore.
FAU - Izumi-Nakaseko, Hiroko
AU  - Izumi-Nakaseko H
AD  - Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo 143-8540, 
      Japan.
FAU - Goto, Ai
AU  - Goto A
AD  - Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo 143-8540, 
      Japan.
FAU - Pang, Jeremy Kah Sheng
AU  - Pang JKS
AD  - Institute of Molecular and Cell Biology, Agency for Science, Technology and 
      Research, Singapore 138673, Singapore.
FAU - Soh, Boon Seng
AU  - Soh BS
AD  - Institute of Molecular and Cell Biology, Agency for Science, Technology and 
      Research, Singapore 138673, Singapore.
AD  - Department of Biological Sciences, Faculty of Science, National University of 
      Singapore, Singapore 117558, Singapore.
FAU - Kojodjojo, Pipin
AU  - Kojodjojo P
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore 119228, Singapore.
FAU - Sugiyama, Atsushi
AU  - Sugiyama A
AD  - Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo 143-8540, 
      Japan.
FAU - Chan, Eric Chun Yong
AU  - Chan ECY
AD  - Department of Pharmacy, Faculty of Science, National University of Singapore, 
      Singapore 117543, Singapore.
LA  - eng
PT  - Journal Article
DEP - 20220316
PL  - Netherlands
TA  - Acta Pharm Sin B
JT  - Acta pharmaceutica Sinica. B
JID - 101600560
PMC - PMC9532722
OTO - NOTNLM
OT  - Arachidonic acid
OT  - Atrial fibrillation
OT  - CYP2J2
OT  - Dronedarone
OT  - Drug-induced proarrhythmia
OT  - Epoxyeicosatrienoic acids
OT  - Mechanism-based inactivation
EDAT- 2022/10/11 06:00
MHDA- 2022/10/11 06:01
PMCR- 2022/03/16
CRDT- 2022/10/10 04:33
PHST- 2021/11/23 00:00 [received]
PHST- 2022/01/13 00:00 [revised]
PHST- 2022/02/21 00:00 [accepted]
PHST- 2022/10/10 04:33 [entrez]
PHST- 2022/10/11 06:00 [pubmed]
PHST- 2022/10/11 06:01 [medline]
PHST- 2022/03/16 00:00 [pmc-release]
AID - S2211-3835(22)00107-1 [pii]
AID - 10.1016/j.apsb.2022.03.008 [doi]
PST - ppublish
SO  - Acta Pharm Sin B. 2022 Oct;12(10):3905-3923. doi: 10.1016/j.apsb.2022.03.008. 
      Epub 2022 Mar 16.