The pharmacokinetics of dronedarone in normolipidemic and hyperlipidemic rats

The objectives of the current study were to characterize the pharmacokinetic profile of dronedarone in the rat, and to examine the effect of hyperlipidemia on its pharmacokinetics. Single doses of dronedarone were administered to rats intravenously (4mg/kg), orally (55mg/kg) and intraperitoneally (65mg/kg). To induce hyperlipidemia, some of the rats were administered intraperitoneal doses of poloxamer 407 before giving an oral dose of dronedarone. After intravenous doses of 4mg/kg dronedarone, plasma clearance and volume of distribution at steady-state were 25.1 +/- 8.09mL/min/kg and 10.8 +/- 4.77L/kg, respectively. After oral doses the maximum plasma concentrations (Cmax) and their median time of attainment (tmax) were 1.87 +/- 1.65mg/mL and 3.5h, respectively. Intraperitoneal administration of 65mg/kg dronedarone base yielded plasma Cmax and median tmax of 0.816 +/- 0.611mg/mL and 3h, respectively. Protein binding was high in NL and HL plasma. Dronedarone is extensively distributed with high volume of distribution in the rat. The drug showed poor bioavailability (<20%) after oral and intraperitoneal administration. The increased plasma concentrations after oral dosing to hyperlipidemic rats appears to be attributable to a direct effect on metabolizing enzymes or transport proteins. Copyright (c) 2016 John Wiley & Sons, Ltd.