评估的吸收、代谢和排泄的单一口服1毫克剂量的Tropifexor在健康男性受试者和浓度依赖的Tropifexor新陈代谢。

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王Wang-Lakshman L,苗族Z, L,顾H,卡根M,顾J,麦克纳马拉E,墙,Woessner R, Camenisch G, Einolf HJ,陈J

评估的吸收、代谢和排泄的单一口服1毫克剂量的Tropifexor在健康男性受试者和浓度依赖的Tropifexor新陈代谢。

药物金属底座Dispos。2021年7月,49 (7):548 - 562。doi: 10.1124 / dmd.120.000349。2021年5月5日Epub。

PubMed ID

33952610 (在PubMed

]

文摘

Tropifexor (NVP-LJN452)是一种高度有效的选择性、非甾体类,non-bile酸farnesoid X受体受体激动剂治疗非酒精性脂肪肝炎。研究了其吸收、代谢和排泄后1毫克口服剂量的[(14)C] tropifexor给四个健康男性受试者。质量平衡达到了大约94%的服用剂量恢复在排泄物通过312小时集合。粪便的排泄tropifexor-related放射性起到了重要作用(大约65%的总剂量)。Tropifexor达到最大血药浓度(Cmax) 33.5 ng / ml的平均时间达到4小时和被淘汰的Cmax等离子消除半衰期为13.5小时。不变tropifexor校长与毒品有关的组件被发现在等离子体(大约92%的总辐射)。两个小氧化代谢物,M11.6 M22.4,观察在流通。Tropifexor被淘汰主要通过新陈代谢> 68%的剂量代谢物在排泄物中恢复过来。氧化代谢似乎tropifexor间隙的主要途径。代谢物包含多个氧化修改和组合氧化和glucuronidation也观察到人类的排泄物。 The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.

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药物靶点

药物	目标	类	生物	药理作用	行动
Tropifexor	胆汁酸受体	蛋白质	人类	未知的	受体激动剂 粘结剂	细节