Ueno Takashi, Ishida Tomomi, Kusano Kazutomi
a Drug Metabolism and Pharmacokinetics , Eisai Co., Ltd , Tsukuba , Ibaraki , Japan.
Xenobiotica. 2019 Jun;49(6):688-697. doi: 10.1080/00498254.2018.1482509. Epub 2018 Jul 5.
The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [C]lemborexant in Sprague-Dawley rats (10 mg/kg) and cynomolgus monkeys (3 mg/kg). In both species, [C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83-1.8 h, and decreased with elimination half-life of 110 h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine. Lemborexant was not detected in bile, urine or faeces, indicating that lemborexant administered orally was completely absorbed from the gastrointestinal tract and that the main elimination pathway was metabolism in both species. In rats, lemborexant was found to be minor in plasma (≤5.2% of total radioactivity), and M9 (hydroxylated form) was the major circulating metabolite. In monkeys, the major circulating components were lemborexant, M4 (N-oxide metabolite), M13 (di-oxidised form), M14 (di-oxidised form) and M16 (glucuronide of mono-oxidised form). In both species, lemborexant was metabolised to various metabolites by multiple pathways, the primary of which was oxidation of the dimethylpyrimidine or fluorophenyl moiety.
新型双食欲素受体拮抗剂lemborexant目前正作为失眠症治疗药物进行研发，在对Sprague-Dawley大鼠（10 mg/kg）和食蟹猴（3 mg/kg）单次口服给予[C]lemborexant后，评估了其处置和代谢情况。在这两个物种中，[C]lemborexant均被快速吸收：血液中的放射性浓度在0.83 - 1.8小时达到峰值，并以110小时的消除半衰期下降。给予的放射性物质主要排泄到粪便中，排泄到尿液中的相对较少。在胆汁、尿液或粪便中未检测到lemborexant，这表明口服给予的lemborexant从胃肠道完全吸收，且两个物种的主要消除途径均为代谢。在大鼠中，lemborexant在血浆中含量较少（≤总放射性的5.2%），M9（羟基化形式）是主要的循环代谢物。在猴子中，主要的循环成分是lemborexant、M4（N-氧化物代谢物）、M13（二氧代形式）、M14（二氧代形式）和M16（单氧代形式的葡糖醛酸苷）。在这两个物种中，lemborexant通过多种途径代谢为各种代谢物，其中主要途径是二甲基嘧啶或氟苯基部分的氧化。
