The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.
Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.
The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUCinf increased in a dose-proportional manner, whereas AUC24h and Cmax exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.
These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.
The prevalence of atrial fibrillation (AF) is forecast to rise to 2–5% of the general population by 2050. Of the two fundamental
treatment strategies for AF management, rhythm control is the approach which is generally preferred for active, symptomatic,
and/or younger patients, whereas rate control is all that is found necessary in the more elderly, sedentary, asymptomatic
individual. In many cases, at neither extreme, there remains a genuine choice of therapy, and for those patients, antiarrhythmic
strategies would be preferred if effective and safe antiarrhythmic medications were available. Many new antiarrhythmic agents
exploiting new mechanisms of action or novel combinations of established antiarrhythmic activity are currently being investigated.
Agents which selectively inhibit ion channels specifically involved in atrial repolarization, so-called atrial repolarization
delaying agents, are widely acknowledged as potentially ideal antiarrhythmic treatments, as they will probably be both effective
and safe, at the very least (free of pro-arrhythmic effects at the ventricular level). Modified analogues of traditional antiarrhythmic
drugs with different combinations of ion channel and receptor blocking effects, novel mechanisms of action, and less complicated
metabolic profiles are also under development. Completely innovative antiarrhythmic agents with new antiarrhythmic mechanisms,
such as stretch receptor antagonism, sodium calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation
are also being explored. In addition, there is increasing evidence in support of the antiarrhythmic action of non-antiarrhythmic
drugs. Treatments with statins, omega-3 fatty acids, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers,
and aldosterone antagonists are all potentially valuable, over and above any effect related to the treatment of underlying
heart disease.
Professor A. John Camm is a consultant to AstraZeneca, Cardiome, sanofi aventis, and Xention. 相似文献
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. 相似文献
A simple, precise, and accurate HPLC method has been developed and validated for the quantitative analysis of Dronedarone Hydrochloride in tablet form. An isocratic separation was achieved using a Waters Symmetry C8 (100 × 4.6 mm), 5 μm particle size column with a flow rate of 1 ml/min and UV detector at 290 nm. The mobile phase consisted of buffer: methanol (40:60 v/v) (buffer: 50 mM KH2PO4 + 1 ml triethylamine in 1 liter water, pH=2.5 adjusted with ortho-phosphoric acid). The method was validated for specificity, linearity, precision, accuracy, robustness, and solution stability. The specificity of the method was determined by assessing interference from the placebo and by stress testing the drug (forced degradation). The method was linear over the concentration range 20–80 μg/ml (r2 = 0.999) with a Limit of Detection (LOD) and Limit of Quantitation (LOQ) of 0.1 and 0.3 μg/ml respectively. The accuracy of the method was between 99.2–100.5%. The method was found to be robust and suitable for the quantitative analysis of Dronedarone Hydrochloride in a tablet formulation. Degradation products resulting from the stress studies did not interfere with the detection of Dronedarone Hydrochloride so the assay is thus stability-indicating. 相似文献
Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment. 相似文献
Introduction: Dronedarone, a derivative of amiodarone with structural modifications, was designed to have similar electrophysiological properties with a less toxic profile.
Areas covered: Brief overview of the pharmacology of dronedarone followed by a summary of randomized clinical trials testing the efficacy of dronedarone in maintaining normal sinus rhythm and clinical outcomes associated with these trials. In depth discussion and commentary on trial findings which may seem contradictory at first approach and brief discussion of post-marketing surveillance studies.
Expert opinion: Dronedarone is a moderately efficacious anti-arrhythmic agent which is safe for use in a carefully selected patient population, maintained in normal sinus rhythm, without advanced congestive heart failure, structural heart disease, permanent atrial fibrillation, digoxin use. It is especially useful in younger patients who lack other risk factors for cardiovascular events and, who stand to gain the most by avoiding long-term pulmonary and thyroid toxicities associated with more effective, but also significantly more toxic agents such as amiodarone. 相似文献
Dronedarone is a new antiarrhythmic agent that has only recently been approved for the therapy of atrial fibrillation (AF). Results regarding a broader spectrum of patients and experience accumulated in clinical practice are still very scarce. Therefore, we prospectively investigated the efficacy and tolerance of dronedarone in a real life setting.
Methods and results
The study included 191 patients (85 women) aged 63 ± 9.9 years with a history of paroxysmal or persistent AF. Follow-up time was 14.3 ± 4.9 months. In patients with persistent AF, sinus rhythm was restored using electrical cardioversion prior to dronedarone administration. Each patient underwent standard ECG on a daily basis during the first 4 days of treatment, and on days 7, 30 and 90, resp. After that, the patients had a follow-up visit every three months. Creatinine, creatine kinase, and hepatic enzymes were closely monitored. Clinical history was meticulously taken at multiple follow-up visits. Dronedarone maintained sinus rhythm in 33.5% (95% CI: 27%–40%), and AF recurrence rate was high: 66.5% (95% CI: 60%–73%). Adverse effects occurred in 31.9% (95% CI: 27%–38%) of the patients and necessitated permanent discontinuation of dronedarone in 22% (95% CI: 17%–27%).
Conclusions
The results suggest that dronedarone may not be superior to available antiarrhythmic agents and caution against its use as a first line therapy in AF. 相似文献