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

ABSTRACT: 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.

SUBMITTER: Karkhanis AV

PROVIDER: S-EPMC9532722 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Karkhanis Aneesh V AV Venkatesan Gopalakrishnan G Kambayashi Ryuichi R Leow Jacqueline Wen Hui JWH Han Marcus Qingrui MQ Izumi-Nakaseko Hiroko H Goto Ai A Pang Jeremy Kah Sheng JKS Soh Boon Seng BS Kojodjojo Pipin P Sugiyama Atsushi A Chan Eric Chun Yong ECY

Acta pharmaceutica Sinica. B 20220316 10

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 <i>via</i> EET enrichment. In this study, we investigate ...[more]

PMID: 36213535

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Project description:The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K(+)) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 muM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD(90)), ventricular effective refractory period (VERP), and transmural conduction time (Deltalatency), where appropriate, were applied to normokalemic (5.2 mM K(+)) and hypokalemic hearts. Hypokalemia increased epicardial APD(90) from 46.6 +/- 1.2 to 53.1 +/- 0.7 ms yet decreased epicardial VERP from 41 +/- 4 to 29 +/- 1 ms, left endocardial APD(90) unchanged (58.2 +/- 3.7 to 56.9 +/- 4.0 ms) yet decreased endocardial VERP from 48 +/- 4 to 29 +/- 2 ms, and left Deltalatency unchanged (1.6 +/- 1.4 to 1.1 +/- 1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD(90) (54.8 +/- 2.7 to 60.6 +/- 2.7 ms), epicardial VERP (84 +/- 5 to 81 +/- 7 ms), endocardial APD(90) (56.6 +/- 4.2 to 63.7 +/- 6.4 ms), endocardial VERP (80 +/- 2 to 84 +/- 4 ms), and Deltalatency (12.5 +/- 6.2 to 7.6 +/- 3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD(90) might diverge sharply from VERP.

Project description:BackgroundAmiodarone and dronedarone are both class III antiarrhythmic medications used to treat arrhythmias. The objective of this study was to enhance the current understanding of adverse drug reaction (ADR) associated with amiodarone and dronedarone by employing data mining methods on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), and providing a reference for safe and reasonable clinical use.MethodsThe ADR records were selected by searching the FAERS database from 2011 Q3 to 2023 Q3. The disproportionality analysis algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were used to detect signals of amiodarone-related and dronedarone-related ADRs. The ADR profiles of amiodarone and dronedarone categorized by organ toxicity were compared through the Z-test and the Fisher exact test.Results9,295 reports specifically mentioned the use of amiodarone and 2,485 reports mentioned the use of dronedarone among 9,972,109 reports, with the majority of ADRs occurring in males over 60 years old. The United States was responsible for the highest proportion of reported ADRs. Significant system organ classes (SOC) for both included Cardiac disorders, Respiratory, thoracic and mediastinal disorders, and Investigations, etc. At the preferred terms (PTs) level, the more frequent ADR signals for amiodarone were drug interaction (n = 856), hyperthyroidism (n = 758), and dyspnoea (n = 607), while dronedarone were atrial fibrillation (n = 371), dyspnoea (n = 204), and blood creatinine increased (n = 123). Notably, unexpected ADRs, including electrocardiogram T wave alternans (n = 16; EBGM05 = 231.27), accessory cardiac pathway (n = 11; EBGM05 = 140), thyroiditis (n = 178; EBGM05 = 125.91) for amiodarone, and cardiac ablation (n = 11; EBGM05 = 31.86), cardioversion (n = 7; EBGM05 = 22.69), and dysphagia (n = 47; EBGM05 = 3.6) for dronedarone, were uncovered in the instructions. The analysis also revealed significant differences in the ADR profiles of amiodarone and dronedarone, with dronedarone showing higher proportions of cardiac toxicity but lower thyroid toxicity compared to amiodarone.ConclusionThese findings underscore the significance of vigilantly monitoring and comprehending the potential risks linked to the use of amiodarone and dronedarone. New ADRs discovered and clear ADR profiles of amiodarone and dronedarone enhance a thorough understanding of these drugs, which is essential for clinicians to ensure safe use of amiodarone and dronedarone.

Dataset Information

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

Publications

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

Similar Datasets

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