【摘要】：目的本研究主要目的在于對硫辛酸進行臨床前毒代動力學的整體評價,比較硫辛酸在不同生物體內(nèi)的毒代動力學差異,為進一步臨床研究提供依據(jù)。方法本文依據(jù)《化學藥物非臨床研究技術指導原則》的基本要求進行全面的方法學考查,對硫辛酸建立了快速靈敏的LC-MS/MS生物樣品定量分析方法。生物樣品經(jīng)過傳統(tǒng)的蛋白沉淀處理。采用華譜XAqua C18(150mm×4.6mm,5um)色譜柱;流動相組成為甲醇(A):水(B),采用梯度洗脫方式,(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,選擇布洛芬作為內(nèi)標。使用ESI離子源的負離子模式和MRM工作方式進行質(zhì)譜分析。結論根據(jù)多劑量口服給予硫辛酸三個劑量組后不同生物體內(nèi)整體暴露水平和AUC0~τ與相應給藥劑量的線性相關性結果,并結合長期毒性試驗結果,可以得出:在硫辛酸低劑量、中劑量及高劑量組三個劑量組多劑量灌胃給藥的長期毒性條件下,不同生物體內(nèi)暴露水平峰值Cmax以及AUC差異,不足以引起對機體明顯損傷,并未造成毒代屬性的明顯變化。硫辛酸在SD大鼠,Beagle犬體內(nèi)毒代動力學呈現(xiàn)線性動力學特征,并且無明顯的藥物蓄積現(xiàn)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，

本文編號：2495637