Department of Non-clinical Pharmacokinetics and Metabolism, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Department of Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Xenobiotica. 2023 Mar;53(3):173-183. doi: 10.1080/00498254.2023.2183159. Epub 2023 May 11.
Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia disorder and has shown improvement in sleep outcomes and daytime functioning. The present work describes its biotransformation pathways and and provides a cross-species comparison between the animal species used in preclinical safety assessments and man.Daridorexant clearance is driven by metabolism along seven distinct pathways. Metabolic profiles were characterised by downstream products while primary metabolic products were of minor importance. The metabolic pattern differed between rodent species, with the rat reflecting the human pattern better than the mouse.In rodents, daridorexant is mostly excreted via the bile after extensive metabolism while urinary excretion was negligible in the rat. Only traces of the parent drug were detected in urine, bile, or faeces.Daridorexant has three major metabolites which are well covered in these preclinical safety species. All of them retain some residual affinity towards orexin receptors. However, none of these is considered to contribute to the pharmacological effect of daridorexant as their active concentrations in the human brain are too low.
达力雷酮是一种双重食欲素受体拮抗剂，用于治疗失眠症，并已显示出改善睡眠结果和日间功能。本工作描述了其生物转化途径，并在用于临床前安全性评估的动物物种与人类之间进行了交叉物种比较。达力雷酮的清除主要通过七种不同途径的代谢来驱动。代谢特征由下游产物来描述，而主要代谢产物的重要性较小。代谢模式在啮齿动物物种之间存在差异，大鼠比小鼠更能反映人类的模式。在啮齿动物中，达力雷酮在广泛代谢后主要通过胆汁排泄，而大鼠的尿排泄可忽略不计。在尿液、胆汁或粪便中仅检测到微量的母体药物。达力雷酮有三个主要代谢物，在这些临床前安全物种中都有很好的描述。它们都保留了对食欲素受体的一些残留亲和力。然而，由于它们在人脑中的有效浓度太低，因此没有一种被认为对达力雷酮的药理作用有贡献。
