Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia
Abstract We 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...
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.1183 |
| _version_ | 1797213353316188160 |
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| author | Yoshihiro Konno Shunsuke Kamigaso Hidetoh Toki Shuichi Terasaka Hirohiko Hikichi Hiromi Endo Jun‐Ichi Yamaguchi Akiko Mizuno‐Yasuhira |
| author_facet | Yoshihiro Konno Shunsuke Kamigaso Hidetoh Toki Shuichi Terasaka Hirohiko Hikichi Hiromi Endo Jun‐Ichi Yamaguchi Akiko Mizuno‐Yasuhira |
| author_sort | Yoshihiro Konno |
| collection | DOAJ |
| description | Abstract We 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 was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next‐day residual effects in humans. |
| first_indexed | 2024-04-24T10:56:56Z |
| format | Article |
| id | doaj.art-f0fdc42495644a57a4587a112985bc33 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-24T10:56:56Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-f0fdc42495644a57a4587a112985bc332024-04-12T05:54:30ZengWileyPharmacology Research & Perspectives2052-17072024-04-01122n/an/a10.1002/prp2.1183Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomniaYoshihiro Konno0Shunsuke Kamigaso1Hidetoh Toki2Shuichi Terasaka3Hirohiko Hikichi4Hiromi Endo5Jun‐Ichi Yamaguchi6Akiko Mizuno‐Yasuhira7Drug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanPharmacology, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanDrug Safety and Pharmacokinetics, Research Center Taisho Pharmaceutical Co., Ltd. Saitama JapanAbstract We 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 was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next‐day residual effects in humans.https://doi.org/10.1002/prp2.1183dispositionhalf‐lifemetabolismorexinpharmacokineticTS‐142 |
| spellingShingle | Yoshihiro Konno Shunsuke Kamigaso Hidetoh Toki Shuichi Terasaka Hirohiko Hikichi Hiromi Endo Jun‐Ichi Yamaguchi Akiko Mizuno‐Yasuhira Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia Pharmacology Research & Perspectives disposition half‐life metabolism orexin pharmacokinetic TS‐142 |
| title | Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia |
| title_full | Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia |
| title_fullStr | Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia |
| title_full_unstemmed | Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia |
| title_short | Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia |
| title_sort | preclinical metabolism and the disposition of vornorexant ts 142 a novel dual orexin 1 2 receptor antagonist for the treatment of insomnia |
| topic | disposition half‐life metabolism orexin pharmacokinetic TS‐142 |
| url | https://doi.org/10.1002/prp2.1183 |
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