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

Abstract

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.

Keywords:

• CS-3150
• MRA
• QWBA
• structure elucidation
• metabolites

Acknowledgements

The authors thank Sekisui Medical Co., Ltd., Shin Nippon Biomedical Laboratories, Ltd., and LSI Medience Corporation for their expert experiments.

Declaration of interest

The authors are employees of Daiichi-Sankyo Co., Ltd. The authors alone are responsible for the content and writing of this article.