Pharmacokinetics And Pharmacodynamics Study Of Ginsenosides In Shexiang Baoxin Pill Based On Metabonomics Approach

Based on Chinese medicine theories,the Traditional Chinese Medicine(TCM)formulas consist of two or more than two Chinese herbal medicines,which are major forms in clinical application.The main characteristics of TCM formulas are multiple components,multiple targets and multiple pathways.TCM formulas acts on the human body is an interaction integrated biological processes of intervention system(TCM formula)-response system(organisms).Under the influence of biological organisms,the intervention system produced absorption,distribution,metabolism and excretion(ADME),whilebiological organisms produced efficacy or toxicity.Pharmacokinetics is one significant method to distinct the composition and function of intervention system.After response system(organisms)affected by intervention system(TCM formula),the endogenous metabolite group will make response,and this response can be accurately characterized with metabonomics.The pharmacokinetics and pharmacodynamics(PK/PD)correlation research based on metabonomics approach can focus on intracorporal process of drugs,drug overall effect,and the relationship between them.The combinations of two system were powerful to provide scientific basis for clarifying the integrated biological processes and integration mechanisms of medicinal material.Five kinds of ginsenosides(Rg1,Rb3,Re,Rc and Re)were selected as analytes to investigate the pharmacokinetic properties of ginsenosides in five mono-therapy groups,GE group and SBP group.Metabonomics approach were used to evaluate the therapeutic effect of five mono-therapy groups,GE group and SBP group,and the PD properties of the seven administered groups were analysed.To analyze the pharmacokinetics and pharmacodynamics characteristics of ginsenosides in SBP and enrich the scientific content of SBP,the effect index of MI was established and analyzes the correlation between biomarkers and five analytes were calculated.The research contents include as following:Firstly,LC-QqQ/MS method was used to analyze plasma samples of each administrated groups in myocardial infarction rats at different time points to obtain the average blood concentrations of all the analytes.The pharmacokinetic parameters of all the analytes were analyzed by noncompartmental analysis.The Tmaxof corresponding analytes between groups revealed that ginsenosides in both SBP and GE were absorbed faster than each of five compounds.While the oral administration doses of each ginsenosides in SBP were the least in all groups,the AUC0-tand AUCINF of each ginsenosides in SBP were the greatest,which indicated that there are ingredients in SBP can promote the absorption of ginsenosides,which reflects the rationality of TCM.Secondly,thirty four kinds of biomarkers were found in the plasma of MI rats based on metabonomics,which were mainly involved in amino acid metabolism,lipid metabolism,arachidonic acid metabolism,purine metabolism.Moreover,these biomarkers were related to energy metabolism disorder,oxidative stress,myocardial hypertrophy and inflammatory reaction process.Among all the thirty four kinds of biomarkers,early biomarker Glycerylphosphorylethanolamine and 5 sustained biomarkers,including 3-Methylxanthine?L-Tyrosine?Sphinganine?L-Phenylalanine and L-Valine,were associated with energy metabolism dysregulation after MI.Above all,it instructed that energy metabolism disorder is a major cause for metabolic abnormalities after MI.The treatment for MI of five ginsenosides mainly by improving the energy metabolism disorder,while GE and SBP had therapeutic effect on myocardial infarction area increases,energy metabolism disorder,inflammation and oxidative damage caused byMI.SBP showed better regulation on improving the oxidative damage,correcting the energy metabolism disorders and inhibiting myocardial infarction area increase than GE.Among all the administration groups,the efficacy evaluations of SBP(except 5 min time point)are optimal at all the different time points.Finally,he PK/PD correlations of ginsenosides in SBP were analyzed based on the above work.To evaluate the comprehensive treatment effect of MI,the curative effect index was established,and the combination index of 5 kinds of ginsenosides in SBP and GE were calculated based on Medium-eflectprinciple,and the correlation coefficient of 5 kinds of ginsenosides with biomarkers in SBP and GE in different time points were analyzed.The results showed that Re,Rc and Rb1 were more closely related to the treatment of SBP in MI.The aera under concentration-time curve(AUCC)of the five kinds of ginsenosides showed a certain correlation with the aera under effect-time curve(AUCE).By calculating the combination index of five kinds ginsenosides in SBP and GE,we found that five kinds ginsenosides in SBP can exert its effect better,which illustrated the rationality of the TCM formula.The results of correlation coefficient of 5 kinds of ginsenosides with biomarkers in SBP showed that five kinds of ginsenosides performed treating effect in MI by correcting energy metabolism disorder.