Dronedarone: the effect of diet-induced obesity on its metabolism and experimental hyperlipidemia on its metabolism and tissue distribution in the rat.

ABSTRACT

Dronedarone biodistribution in hyperlipidemia and dronedarone metabolism in hyperlipidemia or obesity were assessed. Male Sprague-Dawley rats were given either normal standard chow with water or various high-fat or high-carbohydrate diets for 14 weeks. There was also a nonobese hyperlipidemic group given poloxamer 407 intraperitoneally. Liver and intestinal microsomes were prepared and the metabolic conversion of dronedarone to desbutyldronedarone was followed. A biodistribution study of dronedarone given orally was conducted in hyperlipidemic and control normolipidemic rats. The metabolism of dronedarone to desbutyldronedarone in control rats was consistent with substrate inhibition. However in the treatment groups, the formation of desbutyldronedarone did not follow substrate inhibition; hyperlipidemia and high-calorie diets created remarkable changes in dronedarone metabolic profiles and reduction in formation velocities. Tissue concentrations of dronedarone were much higher than in plasma. Furthermore, in hyperlipidemia, plasma and lung dronedarone concentrations were significantly higher compared to normolipidemia.