Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions

Wadhani, Nitin; Sarma, J. S. M.; Singh, Bramah N.; Radzik, David; Gaud, Christine

doi:10.1177/1074248406290678

Cited by 14 publications

(9 citation statements)

References 19 publications

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“…During clinical administration of 400 mg bid, the maximum plasma values of dronedarone range from 84 to 147 ng/ml (approximately 151 to 264 nM), which exceed the WT IhERG IC50 of 42.6 nM in the present study [35]. 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].…”

Section: Relevance Of Potency Of Dronedarone Inhibition Of Ihergcontrasting

confidence: 40%

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

Zhang¹,

Colenso²,

Dempsey

et al. 2018

JICOA

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Dronedarone is a non-iodinated analogue of the Class III antiarrhythmic agent amiodarone. It exerts potent inhibition of "hERG" potassium channels that underpin the cardiac rapid delayed rectifier potassium current, IKr. This study aimed to extend understanding of interactions between dronedarone and the hERG channel. Whole-cell patch-clamp recordings were made at 37C of hERG channel current (IhERG) from HEK-293 cells expressing wild-type (WT) hERG or alanine mutants of residues in the channel's pore-helix/selectivity filter region (T623, S624, V625) or S6 helices (S649, Y652, F656, V659). Molecular docking simulations were performed using a cryo-EM structure of hERG and a MthK-based homology model. The half-maximal inhibitory (IC50) value for WT IhERG inhibition by dronedarone was 42.6 ± 3.9 nM (n= at least 5 cells for each of 6 concentrations). 600 nM dronedarone exerted reduced WT IhERG block when the direction of K + flux was reversed, consistent with interactions between the drug and permeant ion. In contrast with recently reported data for amiodarone, the S624A mutation did not attenuate IhERG blockade, whilst T623A and V625A channels exhibited modestly attenuated block. The S649A mutation was without significant effect and the Y652A and F656A mutations exhibited modest reductions in block. The V659A mutation produced the most marked effect on dronedarone action. Docking simulations were generally consistent with modest interactions with canonical binding residues and suggested an indirect rather than direct effect of the V659A mutation on the drug's action. These findings leave open the possibility that as yet unexplored residue(s) could act as key determinants of high affinity hERG channel block by dronedarone.

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Section: Relevance Of Potency Of Dronedarone Inhibition Of Ihergcontrasting

confidence: 40%

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

Zhang¹,

Colenso²,

Dempsey

et al. 2018

JICOA

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“…; Wadhani et al. ). Dronedarone has obtained a marketing authorization valid throughout the European Union and the United states granted by the European Commission and Food and Drug Administration in 2009.…”

Section: Introductionmentioning

confidence: 98%

“…; Wadhani et al. ) and with the 400‐mg twice daily dose typically used in clinical trials, the PR interval increased by 13.4 msec, and the incidence of any QTc interval >500 msec was 7.7% (Touboul et al. ; Wadhani et al.…”

Section: Introductionmentioning

confidence: 99%

Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug

Klieber

Arabeyre-Fabre

Moliner

et al. 2014

Pharmacology Res & Perspec

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The in vitro metabolism of dronedarone and its major metabolites has been studied in human liver microsomes and cryopreserved hepatocytes in primary culture through the use of specific or total cytochrome P450 (CYP) and monoamine oxidase (MAO) inhibitors. The identification of the main metabolites and enzymes participating in their metabolism was also elucidated by using rhCYP, rhMAO, flavin monooxygenases (rhFMO) and UDP-glucuronosyltransferases (rhUGT) and liquid chromatography/tandem mass spectrometry (LC/MS-MS) analysis. Dronedarone was extensively metabolized in human hepatocytes with a metabolic clearance being almost completely inhibited (98 ± 2%) by 1-aminobenzotriazole. Ketoconazole also inhibited dronedarone metabolism by 89 ± 7%, demonstrating the crucial role of CYP3A in its metabolism. CYP3A isoforms mostly contributed to N-debutylation while hydroxylation on the butyl-benzofuran moiety was catalyzed by CYP2D6. However, hydroxylation on the dibutylamine moiety did not appear to be CYP-dependent. N-debutyl-dronedarone was less rapidly metabolized than dronedarone, the major metabolic pathway being catalyzed by MAO-A to form propanoic acid-dronedarone and phenol-dronedarone. Propanoic acid-dronedarone was metabolized at a similar rate to that of N-debutyl-dronedarone and was predominantly hydroxylated by CYP2C8 and CYP1A1. Phenol-dronedarone was extensively glucuronidated while C-dealkyl-dronedarone was metabolized at a slow rate. The evaluation of the systemic clearance of each metabolic process together with the identification of both the major metabolites and predominant enzyme systems and isoforms involved in the formation and subsequent metabolism of these metabolites has enhanced the overall understanding of metabolism of dronedarone in humans.

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“…Dronedarone and amiodarone are both considered multichannel blockers, as they inhibit fast sodium channels, possess beta adrenergic blocking effects, and inhibit calcium channels [6,7]. Dronedarone can prolong the action potential duration as well as RR, QT, and QTc intervals [6,10]. Unlike amiodarone, dronedarone has no effect on the Na + /K + pump [7].…”

Section: Chemistry Antiarrhythmic Effects and Pharmacokineticsmentioning

confidence: 98%

Dronedarone: A Safety Comparison to Amiodarone

Clem¹,

Farver²,

Fischer³

et al. 2010

CDS

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Dronedarone is an oral Class III antiarrhythmic agent which was recently approved by the US Food and Drug Administration for use in nonpermanent atrial fibrillation. Structurally similar to amiodarone, dronedarone is a benzofuran derivative but it lacks the iodine moiety attached to amiodarone. Based upon the investigational clinical trials to date, it appears that dronedarone has an established efficacy when compared to placebo along with exhibiting a minimal adverse effect profile. The efficacy of dronedarone will need to be further evaluated in comparison trials with established antiarrhythmics for atrial fibrillation. The adverse profile of dronedarone appears to be substantially safer in comparison to amiodarone, although there is still little data available. The adverse effect profile of amiodarone necessitates close and extensive monitoring. Although a risk of pulmonary toxicity was identified in animals, long term studies in humans are needed to determine the significance of this adverse effect with dronedarone. One noted effect of dronedarone is an isolated increase in serum creatinine levels, and the clinical relevance of this effect needs further evaluation. Based on supporting evidence, the use of dronedarone is contraindicated in advanced or decompensated heart failure. Some clinically significant dronedarone drug interactions have been identified. Although the potential differences between dronedarone and amiodarone have been evaluated there have been no direct comparison trials published to date. This article reviews the chemistry, antiarrhythmic effects, pharmacokinetics, efficacy, adverse effects and drug interactions of dronedarone.

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Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions

Cited by 14 publications

References 19 publications

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

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

Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug

Dronedarone: A Safety Comparison to Amiodarone

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