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采用体外肝微粒体孵育体系,研究雌二醇在大鼠、比格犬和人肝微粒体中酶代谢动力学及代谢产物差异。通过对雌二醇浓度、肝微粒体蛋白含量和孵育时间等条件的考察,优化雌二醇与肝微粒体的反应体系;应用LC-MS/MS定量检测孵育体系中的雌二醇及代谢产物,分析比较雌二醇在3个种属、不同性别肝微粒体中代谢产物种类和生成量的差异,计算并比较相应的动力学参数。在3个种属肝微粒体中均发现9个I相代谢产物,且百分比有种属差异。结果表明,3个种属的肝微粒体对雌二醇I相代谢途径基本相同,但是代谢产物的生成量及雌二醇的药物代谢动力学性质存在一定的差异。
The in vitro hepatic microsomal incubation system was used to study the differences in enzyme kinetics and metabolites of estradiol in rat, beagle dog and human liver microsomes. The reaction system of estradiol and liver microsome was optimized through the investigation of estradiol concentration, liver microsomal protein content and incubation time. The estradiol and metabolites in the incubation system were quantitatively determined by LC-MS / MS . The differences of metabolites and production of estradiol in three species and different sex liver microsomes were analyzed and compared. Corresponding kinetic parameters were calculated and compared. Nine I-phase metabolites were found in the three species of liver microsomes, and the percentages were species-specific. The results showed that the liver microsomes of three species had the same metabolic pathways of estradiol I phase, but there were some differences in metabolite production and estradiol pharmacokinetic properties.