Abstract
Esaxerenone (CS-3150) is a novel non-steroidal selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution and excretion (ADME) of esaxerenone was assessed in in vitro studies and a clinical study of [14C]esaxerenone (150 μCi/20 mg) administered orally to 6 healthy male subjects. Plasma concentrations of esaxerenone and metabolites M4, M11 and M1 were measured by LC-MS/MS methods. Recovery of radioactivity was 92.5% with 38.5% and 54.0% excreted in urine and feces, respectively. The half-life of radioactivity in blood and plasma was approximately 30 h and similar to that of the unchanged form in plasma. The blood to plasma ratio was 0.69, demonstrating low partitioning to blood components. In plasma, esaxerenone was the most abundant moiety (40.8%), followed by the metabolites O-glucuronide (21.4%, M4), acyl-glucuronide of amide-bond hydrolysate (8.0%, M11) and deshydroxyethyl form (1.7%, M1). In vitro studies showed that esaxerenone was CYP3A and multiple UGT isoform substrate. The contribution of oxidation to its clearance was approximately 30% as indicated by excretion ratio of oxidized metabolites into urine and feces. Caco-2 studies showed that esaxerenone was both a P-gp and BCRP substrate, however, the excretion ratio of unchanged form in feces and urine was 18.5% and 1.6%, respectively, indicating these transporters do not have an important role in esaxerenone's absorption and elimination. Low urinary excretion of esaxerenone also suggests that the plasma exposure of esaxerenone is not susceptible to renal dysfunction. Multiple elimination pathways including oxidation, glucuronidation, and hydrolysis, and low contribution of transporters indicated limited drug-drug interaction potential.
- clinical pharmacology
- distribution
- drug absorption
- human/clinical
- metabolite identification
- pharmacokinetics
- The American Society for Pharmacology and Experimental Therapeutics