Pharmacokinetics, distribution, and disposition of esaxerenone, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist, in rats and monkeys. (2nd December 2017)

• Record Type: Journal Article
• Authors: Yamada, Makiko; Takei, Makoto; Suzuki, Eiko; Takakusa, Hideo; Kotsuma, Masakatsu; Washio, Takuo; Murayama, Nobuyuki; Inoue, Shin-ichi; Izumi, Takashi
• Is Part Of: Xenobiotica. Volume 47:Number 12(2017)
• Page Start: 1090
• Page End: 1103
• Publication Date: 2017-12-02
• Subjects: CS-3150 -- MRA -- QWBA -- structure elucidation -- metabolites; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2016.1263766
• Languages: English
• ISSNs: 0049-8254

Abstract

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 [ 14 C]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 [ 14 C]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.