| Guizhi fuling capsule is made up with Cinnamomi ramulus,Poria,Moutan cortex,Paeoniae radix alba and Persicae semen,with the role of promoting blood stasis,eliminating symptoms,mainly used for dysmenorrhea,amenorrhea,endometriosis and so on.The research on the unit Chinese medicine has been common,but the systematic research on the quality markers in vivo based on Guizhi fuling capsule is rare.This paper intends to systematically and comprehensively study the quality markers of three herbs of Guizhi fuling capsule from the different producing areas,harvesting periods,drying methods,pharmacokinetic parameters,distribution,metabolism,and excretion.Literature researchA synthetical review was given about the quality markers of three herbs of Guizhi fuling capsule and the change of quality markers in the process of processing and in vivo.It provides theoretical basis to design the experiment scheme to study quality markers.Experimental study1.Study on the quality markers of Poria,Moutan cortex and Paeoniae radix alba1.1 Study on the quality markers of Poria1.1.1 Study on the differences of Poria in different areasWe determined 8 triterpenoid acids in Poria from three producing areas,and it was found that the differences of Poria from three producing areas are the contents of dehydrotumulosic acid,poricoic acid A,polyporenic acid C and dehydropachymic acid.1.1.2 Study on the quality markers of Poria in different harvesting timeWe determined 8 triterpenoid acids,and found that the content of pachymic acid was the highest in triterpenic acid,the contents of pachymic acid and dehydropachymic acid were the highest in early October,and the content of dehydrotomolumoic acid was the highest in early September.1.1.3 Study on the quality markers of Poria in different drying methodsWe determined 8 triterpenoid acids,and found that the cutting specification,sweating time,sweating temperature and drying temperature have little effect on the content of quality markers in Poria,but cutting and sweating shorten the drying time.1.2 Study on the quality markers of Moutan cortex1.2.1 Study on the differences of Moutan cortex in different areasWe established the fingerprint of Moutan cortex from different areas and identified twelve compounds.Through the determination,We found paeonol content was the highest in Shi ba 1i town,while gallic acid,paeoniflorin and benzoyl paeoniflorin content was the highest in Shi jiu li town.1.2.2 Study on the quality markers of Moutan cortex in different harvesting timeWe determined 4 compounds,and found that the content of paeonol was the highest in Moutan cortex around October 30.1.2.3 Study on the quality markers of Moutan cortex in different drying methodsA batch of Moutan cortex were dried at different temperatures under different drying methods.We determined 16 compounds,and found that the content of phenolic components changed the most.With the temperature increasing,the content of paeonol increased first and then decreased.Content of monoterpene glycosides:infrared>microwave>hot air.The content of gallic acid was higher at 40?-60?.The content of quercetin dihydrate and catechin decreased the most after drying.After drying,the content of1,2,3,4,6-penta-O-galloyl-?-D-glucopyranose decreased.1.3 Study on the quality markers of Paeoniae radix alba1.3.1 Study on the differences of Paeoniae radix alba in different areasWe established the fingerprint of Paeoniae radix alba from different areas and identified ten compounds.We found there were four different compounds in the content and identified two of them.We determined of 6 chemical components,and the content of paeoniflorin was the highest in sichuan province,and the content of albiflorin and benzoyl paeoniflorin was the highest in Shanxi Province.1.3.2 Study on the quality markers of Paeoniae radix alba in different harvesting timeWe determined 3 compounds,and found that the content of paeoniflorin was the highest in Paeoniae radix alba around October 30.1.3.3 Study on the quality markers of Paeoniae radix alba in different drying methodsA batch of Paeoniae radix alba were dried at different temperatures under different drying methods.We found that the content of paeoniflorin,albiflorin and benzoyl paeoniflorin increased after poaching,the content of gallic acid and l,2,3,4,6-penta-O-galloyl-?-D-glucopyranose increased and the content of benzoic acid decreased after peeling,the content of paeoniflorin was the highest when dried at 60? hot wind.2.Study on the quality markers of Guizhi fuling capsule based on in vivo process2.1 Identification of the metabolites of quality markers of Guizhi fuling capsule in rat plasma,bile,urine and fecesAs a result,we determined 50 metabolites of gallic acid,paeonol glucoside,paeoniflorin,paeonol,dehydrotumulosic acid,pachymic acid.2.2 Pharmacokinetic study on quality markers of Guizhi fuling capsuleIn order to study the pharmacokinetic quality markers of Guizhi fuling capsule,an UHPLC-LTQ-Orbitrap-MS method had been establised to determine the nine compounds.Meanwhile,a semi-quantitative method method of 3 metabolites based on the preliminary research.It was found that after primary dysmenorrhea model was established,the Cmax of paeonol,aplopaeonoside,albiflorin and oxypaeoniflora significantly increased,while the Cmax of poricoic acid A and dehydrotumulosic acid significantly decreased.The AUC(0-t)of paeonol,aplopaeonoside,paeonol glucoside,gallic acid,albiflorin and oxypaeoniflora significantly increased.2.3 Intestinl absorption studies on quality markers of Guizhi fuling capsuleA intestinl absorption study on different concentration quality markers of Guizhi fuling capsule was carried out,and we found there was no significant difference(P>0.05)in all compounds at different concentration,prompting the compositions diffusing into the systemic circulation passively.It was found that paeonol and gallic acid had higher absorption rate constants,which may be due to their simple molecular structure,small molecular weight,and were easy to be transferred through the cell membrane and absorbed passively.Different intestinl absorption study on quality markers of Guizhi fuling capsule was carried out,and we found the absorption sites of pachymic acid,dehydrotumulosic acid and oxypaeoniflora were mainly in the colon.The absorption parameters of other components had no significant difference(P>0.05),indicating that there was no specific absorption site in the intestine of the model rats.The absorption rate of gallic acid at medium concentration in duodenum,jejunum and ileum was higher than that of other components.Comparing the absorption rate constants of each component in the duodenum at blank and model rats,we found that the absorption rate in the duodenum of gallic acid,paeonol glycosides and oxypaeoniflora increased after constructing primary dysmenorrhea model,while the absorption rate of paeonol decreased.After the addition of p-gp inhibitors to the intestinal perfusion fluid,we found that there were significant differences in the absorption rate constants of gallic acid,dehydrotumulosic acid,paeonol glycosides,paeoniflorin and paeonol(P<0.05).The contents of gallic acid,paeoniflorin and paeonol significantly decreased,while the contents of dehydrotumulosic acid and paeonol glycosides were significantly increased.Therefore,it was speculated that dehydrotumulosic acid and paeonol glycosides could be substrates of p-gp.2.4 Excretion studies on quality markers of Guizhi fuling capsuleRat bile,urine and feces samples were analyzed after gavage of guizhi poria cocos capsule.We calculated the cumulative excretion and cumulative excretion rate,and found that dehydropachymic acid,polyporenic acid C,mudanpioside C,paeoniflorin were excreted mainly through bile.Paeonol,gallic acid and albiflorin were excreted through urine.Pachymic acid,dehydrotumulosic acid,oxypaeoniflora and benzoyl paeoniflorin are excreted mainly through feces. |
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