| SWRG was a clinical formula,which has been mainly proved effective in the treatment of hepatic fibrosis.Based on the previous studies of SWRG,it was necessary to go on the study of physiological disposition to explore the mechanism of its hepatoprotective,and provide support for further clinical studies.The first chapter Literature ReviewedThe second chapter the studies of pharmacokinetics of SWRG in the normal ratsIn this part,there were three sections.The first section the study of pharmacokinetics of the compatibility of the bio-markers in DanshenThere wereTanshinones and Polyphenolics in the formula of SWRG.It is important to investigate the interaction between them.A rapid and highly sensitive UPLC/MS/MSmethod has beenestablished to determine the rat plasma concentrations of the 7 main bioactive compounds including Tanshinone IIA,Tanshinone I,Cryptotanshinone,Salvianolic acid B,Protocatechuic acid,Rosmarinic acid,Danshensu.The method showed good precision,accuracy,recovery,sensitivity,linearity andstability.The tanshinones improved the bioavailability of DSS,speed the elimination rate of RA,Sal B and promote the distribution in vivo.They also contributed to promote the biotransformation of Sal B to DSS.The polyphenolics could affect the pharmacokinetic of tanshinones,especially CT and TSIIA.They also promote the biotransformation of CT to TSIIA.The bioavailability of TSIIA improved.This study may provide useful information to avoid unexpected increase of the plasma drug concentrationin the clinical practice.The second section Pharmacokinetic characteristics of curcumins in compatibility of SWRG in ratsRats were divided into three groups at random,being respectively fed with themixture of curcuminand bisdemethoxycurcumin,curcumin extractand SWRG extract.Plasma samples ofeach group were collected.The contents of curcumin and bisdemethoxycurcumin were measured by UPLC-TQ/MSand they were tested by multiple reaction monition in positive ion.The pharmacokinetic parameters of each group were calculated by DAS 3.2and compared with each other.There were no significant differences betweengroups in T1/2,Tmax;while the Cmax and AUC0～T in FF group was obviously more than these in the TT andHH groups.The MRT0～T of curcumin in TT and FF goups was slightly smaller than that in the HH group.ExpectTmax,there were no obvious differences among pharmacokinetic parameters of bisdemethoxycurcumin.SWRG can increase Cmaxand bioavailability of curcuminand speeds the absorption velocityof bisdemethoxycurcumin but can not change the bioavailability.The third chapter based on CCl4-induced hepatic injury model rats to investigate the mechanism of SWRGIn this part,there were two sections.The first section Comparative study on pharmacokinetics and tissue distribution of major bio-active components in normal and CCl4-induced hepatic injury rats after oral administration of SWRG by UPLC-TQ/MSThis paper copy classic CCl4 hepatic fibrosis in rats by intragastric administration modeling two months,screening out the right hepatic fibrosis in rats were randomly divided into five groups,each six,one group as a pharmacokinetic model group the other four groups for the tissue distribution of the model group,the same group of normal SD rats.A sensitive method was developed to determine Tanshinone I,Tanshinone IIA,Cryptotanshinone,Calycosin,Calycosin glucoside,Formononetin,Ononin,curcumin and double demethoxyhaleniaside-curcumin in plasma,heart,liver,spleen,lung,kidney,brain and thymus by UPLC-TQ/MS.By comparing the model group and the normal group pharmacokinetic parameters found nine active ingredients pathological state pharmacokinetic parameters were changed.Ononin and formononetin AUC was significantly increased,and Calycosin,Calycosin glycosides were no significant differences in AUC,and Cmax and T,i2 appears significant differences.Tanshinone I significantly decreased the AUC,and Tan IIA and Cryptotanshinone significantly increases the bioavailability of curcumin is insignificant,while the dual-go methoxy curcumin were significantly improved bioavailability.Comparing the pharmacokinetics,revealing occurs when the liver disease,metabolic capacity decreased metabolism of substances may be suppressed,so that the drug concentration in plasma,play efficacy.The content of different components in tissue distribution were measured at 5min,30min,60min and 240min in the model group and the normal group rats,indicating the various components in the liver,lung,kidney and spleen and other organs.The liver and the content is relatively high,while pathology under the state of liver disease treatment drugs enrichment helps.It also found in rat pulmonary drug concentration just below the liver,while higher levels of pathological conditions,suggesting that we SWRG potential therapeutic effect against lung disease.The second section Urine and plasma metabonomics study of SWRG to investigate the mechanism of hepatoprotective.Copy the traditionalhepatic fibrosismodel induced byCCl4,according to the clinical doseandcycle.The rats were administered 45 day,plasma and urine of rats was collected every 15 dayand at last after administration serum and tissue for pathological examination of rats was collected too.ALT,AST,HA and the content of Hyp were measured.The results showed that after taking a cycle,the various indicators and pathological states in rat plasma showed recovery trend.Endogenous metabolites of three groups were determined with UPLC-Q-TOF/MS.Pattern recognition methods,including PLS-DA and OPLS-DA,were applied to analyze multivariate data,and T-test was used in significant statistical analysis.Metabolomics research results show that the main metabolite has a significant difference between the normal group lysophosphatidic combination model,bile acids,creatine,and other high-citrulline.Major metabolic pathways including primary bile acid biosynthesis,lipid metabolism,results showed SWRG therapeutic intervention of hepatic fibrosis in rats,metabolic disorders can make different degrees of recovery,reveals its possible role and regulation of metabolic pathways. |
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