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目的 制备20-羟基黄体酮甘油三酯前药(20-DHP-C5-TG),考察该前药经胃肠道吸收通过淋巴转运进入体循环的过程。方法 以黄体酮为原料经还原、选择性氧化得到20-羟基黄体酮(20-DHP),对20-DHP进行亲脂性结构修饰，通过酯键将母药20-DHP与修饰基团连接，得到目标前药20-DHP-C5-TG,经IR、~1H-NMR、13C-NMR对其进行结构表征。取大鼠腹腔注射环己酰亚胺建立乳糜微粒阻断模型，随机分为正常给药组(灌胃给予前药油溶液400 mg/kg体重)、淋巴阻断组(腹腔注射环己酰亚胺3 mg/kg体重，1 h后灌胃给予前药油溶液400 mg/kg体重),分别于给药后5 min、15 min、0.5 h、1 h、2 h、4 h、8 h、12 h取血，采用HPLC法测定正常给药组和淋巴阻断组的药时曲线下面积，计算淋巴转运比例。结果 20-DHP和20-DHP-C5-TG均制备成功，产率分别为42%和44%。20α-DHP-C5-TG前药的淋巴转运比例为90.065%,20β-DHP-C5-TG前药的淋巴转运比例为84.950%。结论 20-DHP-C5-TG前药在体内具有明显的淋巴转运趋势，入血后能够释放出母药。
Abstract：Objective Prepare 20-hydroxyprogesterone triglyceride prodrug 20-DHP-C5-TG and investigate the process of the prodrug entering systemic circulation through lymphatic transport through gastrointestinal absorption. Methods Progesterone was reduced and selectively oxidized to provide 20-hydroxyprogesterone(20-DHP). A lipophilic structural alteration was applied to 20-DHP, the parent drug 20-DHP was joined to the modification group via an ester bond to yield the target prodrug: 20-DHP-C5-TG, which characterized by IR, ~1H-NMR and 13C-NMR. Cycloheximide was injected intrapitoneally into rats to create the chylomicron blocking model, randomly divided into normal administration group(intragastric administrate 400 mg/kg prodrug oil solution) and lymphatic blockade group(3 mg/kg cycloheximide was injected intraperitoneally, and 400 mg/kg prodrug oil solution was given intragastric administration 1 h later). Blood samples were taken at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 12 h after administration. HPLC determine the percentage of lymphatic transport, the area under the curves for the groups receiving regular administration and lymphatic blockage were compared. Results Both 20-DHP and 20-DHP-C5-TG were successfully prepared with yields of 42% and 44%, respectively. Lymphatic transport ratio of 20α-DHP-C5-TG prodrug was 90.065%, and that of 20β-DHP-C5-TG prodrug was 84.950%. Conclusion 20-DHP-C5-TG prodrug have obvious tendency of lymphatic transport in rats, and it can release the parent drug after entering the blood.
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基本信息:
中图分类号:R943
引用信息:
[1]程月璇,闫淑静,李梁云,等.20-羟基黄体酮甘油三酯前药20-DHP-C5-TG的制备及其淋巴转运途径初探[J].新疆医科大学学报,2024,47(10):1398-1405.
基金信息:
国家自然科学基金地区项目(82260696); 新疆维吾尔自治区自然科学基金杰出青年项目(2022D01E54)
2024-10-15
2024-10-15