Pharmacokinetics,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of ¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of ¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.