药学学报, 2014, 49(8): 1169-1174
引用本文:
刘鹏, 郭洪祝, 孙江浩, 徐曼, 郭慧, 孙士丰, 果德安. 土荆皮总二萜酸的代谢产物和代谢途径[J]. 药学学报, 2014, 49(8): 1169-1174.
LIU Peng, GUO Hong-zhu, SUN Jiang-hao, XU Man, GUO Hui, SUN Shi-feng, GUO De-an. Metabolic pathway and metabolites of total diterpene acid isolated from Pseudolarix kaempferi[J]. Acta Pharmaceutica Sinica, 2014, 49(8): 1169-1174.

土荆皮总二萜酸的代谢产物和代谢途径
刘鹏1,2, 郭洪祝1,3, 孙江浩1, 徐曼1, 郭慧1, 孙士丰1, 果德安1
1. 北京大学医学部药学院天然药物学系, 北京 100083;
2. 国家知识产权局, 北京 100088;
3. 北京市药品检验所, 北京 100035
摘要:
综合运用体内实验和多种体外实验模型,初步分析了土荆皮总二萜酸(total diterpene acid,TDA) 的代谢情况。在口服和静脉注射给药实验中,使用HPLC-UV和HPLC-ESI/MSn方法在大鼠血、尿、粪和胆汁 样品中都检测到主要代谢产物土荆皮丙2酸(pseudolaric acid C2,PC2),还可检测到脱甲氧基脱乙酰氧基土荆皮 乙酸(demethoxydeacetoxypseudolaric acid B,DDPB),以及推测为土荆皮丙2酸的葡萄糖苷(PC2G) 的代谢产物,原形药物中的土荆皮丙酸(pseudolaric acid C,PC)、土荆皮甲酸(pseudolaric acid A,PA)、土荆皮甲酸葡萄糖苷(pseudolaric acid A O-β-D glucopyranoside,PAG)、土荆皮乙酸葡萄糖苷(pseudolaric acid B O-β-D glucopyranoside,PBG) 和脱乙酰基土荆皮甲酸(deacetylpseudolaric acid A,DPA) 也可以检测到。实验表明,TDA的代谢与肠内菌无关,胃蛋白酶和胰蛋白酶不是主导TDA代谢的因素,在胃、肠道的pH环境下TDA也是稳定的。TDA在体外全血孵育模型中的主要代谢产物是PC2、DDPB和PC2G,证明TDA在体内的代谢转化反应主要是在血液中完成的,并且主要归结于血浆酯酶对酯键的水解以及葡萄糖苷化反应。这一发现首次初步阐明了TDA在体内的代谢途径,对于明确土荆皮的有效物质基础、体内活性形式及其作用机制都具有非常重要的意义。
关键词:    土荆皮      总二萜酸      土荆皮乙酸      土荆皮丙2      脱甲氧基脱乙酰氧基土荆皮乙酸     
Metabolic pathway and metabolites of total diterpene acid isolated from Pseudolarix kaempferi
LIU Peng1,2, GUO Hong-zhu1,3, SUN Jiang-hao1, XU Man1, GUO Hui1, SUN Shi-feng1, GUO De-an1
1. Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083, China;
2. State Intellectual Property Office of People's Republic of China, Beijing 100088, China;
3. Beijing Institute for Drug Control, Beijing 100035, China
Abstract:
The preliminary metabolic profile of total diterpene acid (TDA) isolated from Pseudolarix kaempferi was investigated by using in vivo and in vitro tests. Pseudolaric acid C2 (PC2) was identified as the predominant metabolite in plasma, urine, bile and feces after both oral and intravenous administrations to rats using HPLC-UV and HPLC-ESI/MSn, and demethoxydeacetoxypseudolaric acid B (DDPB), a metabolite proposed to be the glucoside of PC2 (PC2G), as well as pseudolaric acid C (PC), pseudolaric acid A (PA), pseudolaric acid A O-β-D glucopyranoside (PAG), pseudolaric acid B O-β-D glucopyranoside (PBG) and deacetylpseudolaric acid A (DPA) originated from TDA could also be detected. It was demonstrated by tests that the metabolism of TDA is independent of intestinal microflora, and neither of pepsin and trypsin is in charge of metabolism of TDA, TDA is also stable in both pH environments of gastric tract and intestinal tract. The metabolites of TDA in whole blood in vitro incubation were found to be PC2, DDPB and PC2G, which demonstrated that the metabolic reaction of TDA in vivo is mainly occurred in blood and contributed to be the hydrolysis of plasma esterase to ester bond, as well as the glucosylation reaction. These results clarified the metabolic pathway of TDA for the first time, which is of great significance to the in vivo active form and acting mechanism research of P. kaempferi.
Key words:    Pseudolarix kaempferi    total diterpene acid    pseudolaric acid B    pseudolaric acid C2    demethoxydeacetoxypseudolaric acid B   
收稿日期: 2014-02-08
基金项目: 国家高技术研究发展计划(863计划) 资助项目(2003AA2Z2030);教育部长江学者和创新团队发展计划资助项目(985-2-063-112)
通讯作者: 郭洪祝 Tel/Fax:86-10-83226434,E-mail:guohz@bidc.org.cn;果德安 Tel/Fax:86-10-82801516,E-mail:daguo@simm.ac.cn
Email: guohz@bidc.org.cn
相关功能
PDF(524KB) Free
打印本文
0
作者相关文章
刘鹏  在本刊中的所有文章
郭洪祝  在本刊中的所有文章
孙江浩  在本刊中的所有文章
徐曼  在本刊中的所有文章
郭慧  在本刊中的所有文章
孙士丰  在本刊中的所有文章
果德安  在本刊中的所有文章

参考文献:
[1] Liu P, Xu M, Guo HZ, et al. Metabolic pathway and metabolites of pseudolaric acid B [J]. Acta Pharm Sin (药 学学报), 2011, 46: 1361-1365.
[2] Zhang BL, Gao XM, Shang HC, et al. Study on pharmaceutical matters and functional mechanisms of complex prescriptions of Radix Salvial Milti Orrhizal [J]. World Sci Technol-Mod Tradit Chin Med (世界科学技术-中医药现代化), 2003, 5: 14-17.
[3] Liu P, Guo H, Guo HZ, et al. Simultaneous determination of seven major diterpenoids in Pseudolarix kaempferi by high-performance liquid chromatography DAD method [J]. J Pharm Biomed Anal, 2007, 44: 730-736.
[4] Kinouchi T, Kataoka K, Miyanishi K, et al. Biological activities of the intestinal microflora in mice treated with antibiotics or untreated and the effects of the microflora on absorption and metabolic activation of orally administered glutathione conjugates of K-region epoxides of 1-nitropyrene [J]. Carcinogenesis, 1993, 14: 869-874.
[5] Xing J, Chen XY, Sun YM, et al. Interaction of baicalin and baicalein with antibiotics in the gastrointestinal tract [J]. J Pharm Pharmacol, 2005, 57: 743-750.
[6] Chinese Pharmacopeia Commission. Pharmacopeia of the Peoples Republic of China (中华人民共和国药典) [S]. 2005 ed. Part II. Beijing: Chemical Industry Press, 2005: Appendix 72, 158.
[7] Feng WZ, Lu YP. Metabolic degradation of cabexate mesilate in whole blood in vitro [J]. J Guangdong Coll Pharm (广东药学院学报), 1998, 14: 30-32.
[8] Liu P, Sun JH, Xu M, et al. Characterization of diterpenoids in the bark of Pseudolarix kaempferi by HPLC-ESI/MSn [J]. Acta Pharm Sin (药学学报), 2011, 46: 213-220.
[9] Li ZL, Pan DJ, Hu CQ, et al. Chemical structure identifica-tion of pseudolaric acid A and pseudolaric acid B [J]. Acta Chim Sin (化学学报), 1982, 40: 447-457.
[10] Liu P, Guo HZ, Wang WX, et al. Cytotoxic diterpenoids from the bark of Pseudolarix kaempferi and their structure-activity relationships [J]. J Nat Prod, 2007, 70: 533-537.
[11] Li E, Clark AM, Hufford CD. Antifungal evaluation of pseudolaric acid B, a major constituent of Pseudolarix kaempferi [J]. J Nat Prod, 1995, 58: 57-67.
相关文献:
1.刘 鹏 徐 曼 郭洪祝 孙江浩 郭 慧 孙士丰 果德安.土荆皮乙酸的代谢产物和代谢途径[J]. 药学学报, 2011,46(11): 1361-1365