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.

中文翻译：

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vornorexant/TS-142（一种用于治疗失眠的新型双食欲素 1/2 受体拮抗剂）的临床前代谢和处置


我们研究了 vornorexant（一种新型双重食欲素受体拮抗剂）在大鼠和狗中的代谢和处置，并阐明了人类的体外代谢谱。此外，我们研究了大鼠和狗活性代谢物的药代动力学及其在大鼠中枢神经系统的分布，以阐明其对药物疗效的贡献。 [ 14 C]vornorexant在大鼠和狗口服后被迅速且大部分吸收。药物衍生的放射性，包括代谢物，分布到大鼠的肝脏、肾脏等主要器官，并且在这两个物种的给药后 24 小时内几乎被消除。代谢物分析显示 vornorexant 的主要清除机制是通过多种氧化途径进行代谢。主要的循环成分是大鼠中的裂解代谢物（M10、M12），以及狗中的未改变形式，其次是M1，然后是M3。与人肝细胞一起孵育会导致代谢物的形成，包括 M1、M3、M10 和 M12。所有测试物种的代谢途径相似。从药理活性较弱的活性代谢物（M1和M3）的PK和CNS分布来看，大鼠脑脊液和狗血浆中原形的浓度高于活性代谢物，表明原形主要贡献于药物功效。这些研究结果表明，vornorexant 在给药后立即被吸收，并且 vornorexant 及其代谢物在大鼠和狗体内迅速且完全消除。因此，vornorexant 作为催眠药物可能具有良好的药代动力学特征，可在人体中提供快速起效和最小的次日残留效应。