title: 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.
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kotsuma
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Washio
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Murayama
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Inoue
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D008252:Macaca fascicularis / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D000451:Mineralocorticoid Receptor Antagonists / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D051381:Rats; D013450:Sulfones / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011758:Pyrroles; D013450:Sulfones; C000607547:esaxerenone
keywords: CS-3150; MRA; QWBA; metabolites; structure elucidation