BACKGROUND E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. OBJECTIVE We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). . METHODS Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. RESULTS The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. CONCLUSION These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

中文翻译：

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E2，G2的体外代谢：新型胆汁酸耦合喜树碱类似物，在大鼠肝微粒体中。

背景技术E2（喜树碱-20（S）-O-甘氨酸-脱氧胆酸）和G2（喜树碱-20（S）-O-乙酸-脱氧胆酸）是通过在20中引入脱氧胆酸而衍生的两个新的胆汁酸喜树碱类似物。 CPT（喜树碱）在体内具有较高的抗癌活性和较低的系统毒性。目的我们旨在研究大鼠肝微粒体（RLM）对E2和G2的代谢。。方法分别在大鼠肝微粒体中进行E2和G2的Ⅰ期和Ⅱ期代谢，并对E2和G2的Ⅰ期和Ⅱ期代谢进行混合培养。通过液相色谱/质谱法鉴定代谢物。结果结果表明，I期代谢是E2和G2的主要生物转化途径。参与其代谢的同工酶存在一定差异。G2的固有清除率为174.7mL / min。毫克蛋白质，是E2（51.3 mL / min。毫克蛋白质）的三倍以上，表明E2的新陈代谢稳定性更高。检测到10种E2代谢物和14种G2代谢物，包括I期代谢物（主要通过羟基化和水解）及其进一步的葡萄糖醛酸化产物。结论这些发现表明，E2和G2具有相似的生物转化途径，但其酯键和氨基键与母体化合物的水解能力有所不同，这可能导致它们的代谢稳定性和负责任的CYPs（细胞色素P450蛋白）的多样性。表示E2的新陈代谢稳定性更高。检测到10种E2代谢物和14种G2代谢物，包括I期代谢物（主要通过羟基化和水解）及其进一步的葡萄糖醛酸化产物。结论这些发现表明，E2和G2具有相似的生物转化途径，但其酯键和氨基键与母体化合物的水解能力有所不同，这可能导致它们的代谢稳定性和负责任的CYPs（细胞色素P450蛋白）的多样性。表示E2的新陈代谢稳定性更高。检测到10种E2代谢物和14种G2代谢物，包括I期代谢物（主要通过羟基化和水解）及其进一步的葡萄糖醛酸化产物。结论这些发现表明，E2和G2具有相似的生物转化途径，但其酯键和氨基键与母体化合物的水解能力有所不同，这可能导致它们的代谢稳定性和负责任的CYPs（细胞色素P450蛋白）的多样性。