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。
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 incharge 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 ofP. kaempferi.
出处
《药学学报》
CAS
CSCD
北大核心
2014年第8期1169-1174,共6页
Acta Pharmaceutica Sinica
基金
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)
