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

• Published in: Xenobiotica Vol. 47; no. 12; pp. 1090 - 1103
• Main Authors: Yamada, Makiko, Takei, Makoto, Suzuki, Eiko, Takakusa, Hideo, Kotsuma, Masakatsu, Washio, Takuo, Murayama, Nobuyuki, Inoue, Shin-ichi, Izumi, Takashi
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.12.2017
• Subjects: Administration, Oral; Animals; Biological Availability; CS-3150; Macaca fascicularis - metabolism; Male; Metabolic Clearance Rate; metabolites; Mineralocorticoid Receptor Antagonists - pharmacokinetics; MRA; Pyrroles - pharmacokinetics; QWBA; Rats; structure elucidation; Sulfones - pharmacokinetics; Tissue Distribution; CS-3150; QWBA; structure elucidation; MRA; metabolites
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2016.1263766

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.