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In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes
Recent Patents on Anti-Cancer Drug Discovery ( IF 2.8 ) Pub Date : 2021-05-01 , DOI: 10.2174/1574892816666210204122028
Xiangli, Zhang

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, modified deoxycholic acid at 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 174.7 mL/min. mg protein, more than three times 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 for some differences 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:

E2、G2 的体外代谢:大鼠肝微粒体中的新型胆汁酸偶联喜树碱类似物

背景: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)是两种新型胆汁酸衍生的喜树碱类似物,修饰的脱氧胆酸在CPT(喜树碱)的 20 位具有更强的抗癌活性和更低的体内系统毒性。

目的:我们旨在通过大鼠肝微粒体 (RLM) 研究 E2 和 G2 的代谢。

方法:分别进行大鼠肝微粒体中E2和G2的I期和II期代谢,同时处理E2和G2的I期和II期代谢的混合培养。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 的内在清除率为 174.7 mL/min。mg蛋白,是E2的三倍多(51.3 mL/min.mg蛋白),表明E2的代谢稳定性更高。检测到 E2 的 10 种代谢物和 G2 的 14 种代谢物,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:这些研究结果表明,E2和G2具有相似的生物转化途径,除了对母体化合物的酯键和氨基键的水解能力存在一些差异,这可能导致它们的代谢稳定性和负责的CYPs(细胞色素P450蛋白)的多样性。 )。

更新日期:2021-05-01
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