使用UPLC-MS/MS对VX-150活性代谢物的定量分析:在老鼠中进行的一项临床前药理动力学研究
Xia Feng1, Chao Ma1, Zhihui Zhang1
1Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Biomedical chromatography : BMC
|October 14, 2025
概括
选择性NaV1.8抑制剂VX-150M在老鼠中显示出中度的口服生物可用性 (26.67%-36.11%). 它的药用动力学特征,以快速吸收和低清除为特征,支持对潜在的治疗应用的持续开发.
科学领域:
- 药理学和毒理学 药理学和毒理学
- 药物代谢和药理动力学
背景情况:
- VX-150是一种口服前药,迅速转化为其活性代谢物VX-150M.
- VX-150M是一种高度选择性的NaV1.8.8道阻断剂.
研究的目的:
- 描述VX-150M在老鼠中的体外特性和体内药理动力学.
- 开发和验证一种用于在大鼠血中确定VX-150M的生物分析方法.
- 为了确定VX-150M的体外-体内相关性.
主要方法:
- 在大鼠血中开发和验证液态染色学-并联质谱 (LC-MS/MS) 测定VX-150M的测定方法.
- 在体外表征包括Caco-2细胞透性,血蛋白结合,以及人类肝脏显微体中的代谢稳定性.
- 在静脉和口服服用VX-150M后,对大鼠进行了体内药理学研究.
主要成果:
- LC-MS/MS方法已被验证用于在1-2000 ng/mL范围内的大鼠血中量化VX-150M.
- 在静脉注射后,VX-150M的终端半衰期为1.33小时,清除率低 (8.91毫升/分钟/千克).
- 口服导致0.19-0.36小时内的峰值度,线性暴露和口服生物利用率在26.67%至36.11%之间.
- 试验室研究显示,Caco-2的透性中度 (6.1 × 10−6 cm/s),高血蛋白结合 (96.2%-97.5%),以及低代谢周转率.
结论:
- 经过验证的LC-MS/MS方法使得VX-150M在老鼠血中可靠量化.
- VX-150M具有有利的药理动力学特性,包括快速吸收和适度的口服生物可用性.
- 试验室数据为VX-150M的行为提供了洞察力,支持其进一步发展.
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