Yu Zongjiang, Sun Weizhi, Peng Weibing, Yu Rilei, Li Guoqiang, Jiang Tao
Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences , Qingdao 266101, China.
Mol Pharm. 2016 May 2;13(5):1699-710. doi: 10.1021/acs.molpharmaceut.6b00129. Epub 2016 Apr 5.
Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two OA prodrugs (1,3-cyclic propanyl phosphate esters of OA) were designed and synthesized. The hepatoprotective effects of these prodrugs were evaluated against carbon tetrachloride (CCl4) induced liver injury in mice; the levels of alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and aspartate aminotransferase (AST) were significantly increased, and the level of the hepatic malondialdehyde (MDA) was increased. The metabolism, in vitro, of the prodrugs was studied by incubation in rat liver microsome; the plasma pharmacokinetics and the biodistribution in vivo after intravenous (iv) injection to six rats were investigated, respectively. The prodrugs diminished gradually with time; most of the parent drugs were released within 30 min in vitro, and the presumed mechanism of the in vitro metabolism was confirmed. The plasma-concentration data in vivo was analyzed by a compartmental method: both the prodrugs and the corresponding released parent drugs existed at up to 48 h in rats. The t1/2 improved after intravenous administration in rats compared with direct injection of the parent drugs. All analyte concentrations were highest in the liver, and most of the prodrugs were excreted in feces (>47.11%). Therefore, 1,3-cyclic propanyl phosphate esters of OA can serve as a promising lead candidate for drugs.
齐墩果酸（OA）是一种著名的五环三萜类化合物，已被用作膳食补充剂，并作为非处方药用于治疗人类肝脏疾病。这些都是OA生物利用度低的原因，限制了其更广泛的应用。在本研究中，设计并合成了两种OA前药（OA的1,3-环丙基磷酸酯）。评估了这些前药对四氯化碳（CCl4）诱导的小鼠肝损伤的保肝作用；丙氨酸转氨酶（ALT）、乳酸脱氢酶（LDH）和天冬氨酸转氨酶（AST）水平显著升高，肝丙二醛（MDA）水平升高。通过在大鼠肝微粒体中孵育研究了前药的体外代谢；分别研究了静脉注射（iv）给六只大鼠后体内的血浆药代动力学和生物分布。前药随时间逐渐减少；大多数母体药物在体外30分钟内释放，并证实了体外代谢的推测机制。用房室模型法分析体内血浆浓度数据：前药和相应释放的母体药物在大鼠体内均存在长达48小时。与直接注射母体药物相比，大鼠静脉给药后t1/2有所改善。所有分析物浓度在肝脏中最高，大多数前药通过粪便排泄（>47.11%）。因此，OA的1,3-环丙基磷酸酯可作为一种有前景的药物先导候选物。
