阿德福韦混膦酯衍生物体外代谢及稳定性研究

采用超高效液相-飞行时间质谱仪(UPLC-QTOF-MS/MS)和超高效液相-三重四极杆质谱仪(UPLC-MS/MS)考察阿德福韦混膦酯衍生物阿德福韦单L-硫代异亮氨酸乙酯、去氧胆酸丙酯(Q₃-I₂)的稳定性及体外代谢产物，将Q₃-I₂和对照药阿德福韦酯与人工胃液、人工肠液、大鼠空白血浆和大鼠肝微粒体进行体外共孵育，采用UPLC-MS/MS和UPLC-QTOF-MS分别测定各孵育体系中的化合物剩余质量浓度和肝微粒体体系中的代谢产物，并通过底物消除法计算半衰期和清除率。化合物Q₃-I₂在胃肠道中稳定，延长了血浆、肝微粒体半衰期，同时能降解出活性代谢产物。在体外肝微粒体孵育体系中通过UPLC-QTOF-MS正负离子模式共检测到8种代谢产物，主要包括水解、氧化、乙酰化、葡萄糖醛酸化反应。

In vitro metabolism and stability of adefovir mixed phosphonate derivative Q3-I2

A, UPLC-QTOF-MS/MS and UPLC-MS/MS were used to investigate the derivative of adefovir mixed phosphonate Q₃-I₂. Stability and in vitro metabolites of Q₃-I₂, and the control drug adefovir dipivoxil were co-inculbated with artificial gastric juice, artificial intestinal juice, rat blank plasma and rat liver microsomes, using UPLC-MS/MS and UPLC-QTOF-MS/MS measure the residual concentration of the compounds in each incubation system and the metabolites in the liver microsomal system, respectively, and calculate the half-life and clearance rate by the substrate elimination method. The compounds designed and synthesized in this experiment are stable in the gastrointestinal tract, prolonging t1/2 of plasma and liver microsomes and rapidly degrading the active meta-bolites. In the liver microsomal system, a total of 8 metabolites were detected by positive and negative ion mode, including hydrolysis, oxidation, acetylation, and glucuronidation.