Preclinical metabolism and the disposition of vornorexant/TS ‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia

Proposed metabolic pathways of vornorexant are presented. Vornorexant is rapidly absorbed and undergoes extensive metabolism. Vornorexant and its metabolites are rapidly eliminated without tissue residue. The unchanged form mainly contributes to the drug efficacy. AbstractWe investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in  vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug-derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24  h post-dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form wa...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research