硫辛酸的体内药物分析及其临床前毒代动力学研究

发布时间：2019-06-09 14:54

【摘要】：目的本研究主要目的在于对硫辛酸进行临床前毒代动力学的整体评价,比较硫辛酸在不同生物体内的毒代动力学差异,为进一步临床研究提供依据。方法本文依据《化学药物非临床研究技术指导原则》的基本要求进行全面的方法学考查,对硫辛酸建立了快速灵敏的LC-MS/MS生物样品定量分析方法。生物样品经过传统的蛋白沉淀处理。采用华谱XAqua C18(150mm×4.6mm,5um)色谱柱;流动相组成为甲醇(A):水(B),采用梯度洗脱方式,(0min,20%A;0~2min,20%A~20%A;2.01~3.00min,20%A~95%A;3.01~7.00min,95%A~95%A;7.01~9.00mi n,20%A~20%A).流速1.0mL/min,采用2:1分流,选择布洛芬作为内标。使用ESI离子源的负离子模式和MRM工作方式进行质谱分析。结论根据多剂量口服给予硫辛酸三个剂量组后不同生物体内整体暴露水平和AUC0~τ与相应给药剂量的线性相关性结果,并结合长期毒性试验结果,可以得出:在硫辛酸低剂量、中剂量及高剂量组三个剂量组多剂量灌胃给药的长期毒性条件下,不同生物体内暴露水平峰值Cmax以及AUC差异,不足以引起对机体明显损伤,并未造成毒代属性的明显变化。硫辛酸在SD大鼠,Beagle犬体内毒代动力学呈现线性动力学特征,并且无明显的药物蓄积现象。
[Abstract]:Objective the main purpose of this study was to evaluate the preclinical toxicokinetics of lipoic acid and to compare the toxic kinetics of lipoic acid in different organisms, so as to provide evidence for further clinical research. Methods according to the basic requirements of "Technical guiding principles for non-clinical Research of Chemical drugs", a rapid and sensitive method for quantitative analysis of LC-MS/MS biological samples was established in this paper. Biological samples are treated by traditional protein precipitation. A XAqua C18 (150mm 脳 4.6mm, 5um) column was used, and the mobile phase composition was methanol (A): water (B), by gradient elution. at 0 min, 20% A 鈮，

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