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  

Preparation of 20-hydroxyprogesterone (20-DHP) triglyceride prodrug 20-DHP-C5-TG and study on its lymphatic transport pathway

作　　者：程月璇 闫淑静 李梁云 仲春红 陈春丽[1,2,3] 高晓黎[1,2,3] CHENG Yuexuan;YAN Shujing;LI Liangyun;ZHONG Chunhong;CHEN Chunli;GAO Xiaoli(College of Pharmacy,Xinjiang Medical University;Engineering Research Center of Xinjiang and Central Asia Characteristic Pharmaceutical Resources,Ministry of Education;Xinjiang Key Laboratory of Active Components and Drug Release Technology of Natural Medicines,Urumqi 830017,China)

机构地区：[1]新疆医科大学药学院 [2]新疆医科大学新疆及中亚特色医药资源教育部工程研究中心 [3]新疆医科大学新疆天然药物活性组分与释药技术重点实验室,乌鲁木齐830017

出　　处：《新疆医科大学学报》2024年第10期1398-1405,共8页Journal of Xinjiang Medical University

基　　金：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)。

摘　　要：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、1 H-NMR、13 C-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。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,1 H-NMR and 13 C-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.

关 键 词：20-羟基黄体酮 甘油三酯前药 淋巴转运 

分 类 号：R941[医药卫生—药剂学]