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 [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 [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.

Pharmacokinetics, Metabolism, and Excretion of [14C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

“…Two radioactive peaks of the metabolites M4 and M11 were detected. M4 was identified to the O-glucuronide of esaxerenone, similar to that found in monkey plasma (Yamada et al, 2017). The structure of M4 is shown in Fig.…”

“…The product ion at m/z 312 also corresponded to the methyl-(trifluoromethyl)phenyl-hydroxyethyl-pyrrole carboxylate, suggesting that M11 was a glucuronide of the esaxerenone amide-bond hydrolysate. By comparing the retention time and LC-MS/MS spectra with those of the authentic standard, M11 was identified as the acyl-glucuronide of esaxerenone amide-bond hydrolysate; M1, which was identified in rat plasma (Yamada et al, 2017), was detected only by MS and was not detected by radiochromatography.…”

“…In clinical studies, esaxerenone dose dependently reduced blood pressure in patients with hypertension (submitted manuscript); furthermore, the reduction of urinary albumin in patients with type 2 diabetes with microalbuminuria underscores its renal protective effects (submitted manuscript). In pharmacokinetic studies, the absolute oral bioavailability of esaxerenone was high in rats and monkeys (Yamada et al, 2017). The elimination half-life at the terminal phase (t 1/2 ) of esaxerenone in plasma is longer than that of spironolactone and eplerenone in rats, and is considered to contribute to its long-lasting pharmacological effects.…”

“…The elimination half-life at the terminal phase (t 1/2 ) of esaxerenone in plasma is longer than that of spironolactone and eplerenone in rats, and is considered to contribute to its long-lasting pharmacological effects. In rats, orally administered [ 14 C]esaxerenone was distributed widely to tissues, with the exception of a low distribution to the central nervous system (Yamada et al, 2017). After the oral administration of [ 14 C]esaxerenone, the major elimination pathway was oxidation in rats, and oxidation and glucuronidation in monkeys, and the radioactivity was excreted mainly in the feces (Yamada et al, 2017).…”

“…In rats, orally administered [ 14 C]esaxerenone was distributed widely to tissues, with the exception of a low distribution to the central nervous system (Yamada et al, 2017). After the oral administration of [ 14 C]esaxerenone, the major elimination pathway was oxidation in rats, and oxidation and glucuronidation in monkeys, and the radioactivity was excreted mainly in the feces (Yamada et al, 2017). In phase 1 studies, the exposure of esaxerenone after single (5-200 mg/d) and multiple (10-100 mg/d) doses was generally proportional to the dose (Kato et al, 2018).…”