In vivo Analysis of the Anti-atrial Fibrillatory, Proarrhythmic and Cardiodepressive Profiles of Dronedarone as a Guide for Safety Pharmacological Evaluation of Antiarrhythmic Drugs

Abstract

Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (n = 4) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca, Na and K channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the T-T in a dose-related manner with a tendency to prolong the terminal repolarization period and J-Tc, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs.

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

“…Previously, we replicated anti-atrial fibrillatory effects of dronedarone and poyendarone in healthy 38 , 39 and paroxysmal AF dogs 40 . Dronedarone delayed atrioventricular (AV) and intraventricular (IV) conduction and ventricular repolarization and displayed moderate atrial selectivity.…”

“…Early evidence from in vitro patch-clamp and BTB variability experiments signaled a favorable antiarrhythmic and reduced proarrhythmic risk of poyendarone. To confirm these effects in vivo , poyendarone and dronedarone were studied previously in healthy dogs 38 , 39 and in canine model of paroxysmal AF induced by chronic atrioventricular block 40 . Poyendarone showed atrial selectivity and lacked ventricular proarrhythmic propensity in both studies.…”

“…Dronedarone delayed atrioventricular (AV) and intraventricular (IV) conduction and ventricular repolarization and displayed moderate atrial selectivity. Interestingly, poyendarone displayed 1.7-fold greater atrial selectivity compared to dronedarone in addition to the delays in AV and IV conduction 38 , 39 . Dronedarone also significantly prolonged the phase-3 repolarization period possibly due to modest induction of Ca 2+ overload while poyendarone hardly altered phase-3 repolarization period suggesting a lack of Ca 2+ overload 48 .…”

<i>In vivo</i> analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events

“…In our previous studies using the same protocol, amiodarone, dronedarone, donepezil and oseltamivir prolonged the QTcV by 19, 41, 42 and 20 (Matsukura et al, 2017;Motokawa et al, 2018;Hagiwara-Nagasawa et al, 2021;Kitahara et al, 2013). Meanwhile, these drugs did not induce TdP in the chronic atrioventricular block dogs, one of the well-established proarrhythmia models (Yoshida et al, 2002;Kambayashi et al, 2021;Hagiwara-Nagasawa et al, 2021;Nakamura et al, 2016).…”

An exploration of interactions between the antiarrhythmic drug dronedarone and hERG potassium channel pore

“…Dronedarone has been reported to produce concentrationdependent QT interval prolongation in healthy volunteers and cases of excessive QTc prolongation, ventricular ectopy and Torsades de Pointes have been reported in patients receiving dronedarone [36][37][38]. In a recent preclinical study of dogs receiving dronedarone, the drug was found to prolong the Tpeak-Tend interval in a dose-related fashion, suggestive of a propensity to prolong transmural dispersion of repolarization and likely to result from IKr inhibition [39]. Thus, the fact that dronedarone is a potent IhERG blocker likely has relevance to both clinical and pathophysiological effects of the drug and it is prudent that the concurrent presence of other risk factors for drug-induced QT interval prolongation should be taken into account when considering administration of this drug [7,40].…”