Study On The Serum Pharmacochemistryand Pharmacokinetics Of Xiaojin Capsule

XiaoJin Capsule(XJC),originated since Qing dynasty in China,has been proved to have the effects of loosening swelling and analgesia.XJC is prepared from ten medical materials,including artificial Moschus berezovskii,Aconitum kusnezoffii,Liquidambaris resina,Boszvellia carterii,Commiphora myrrha,Angelica sinensis,Faeces trogopterori,Pheretima aspergillum and Fragrant ink.It is suitable for the treatment of mammary gland hyperplasia,thyroid nodules,breast cancer,benign prostatic hyperplasia.However,the chemical composition of XJC in vivo has not been fully defined and the pharmacokinetic characteristics of the main components in vivo have not been clarified.The lack of basic research has limited the further interpretation of the mechanism and hindered the industrialization and internationalization of XJC.Objective:In this study,XJC was chosen as the research target.Based on the theory of serum pharmacochemistry of traditional Chinese medicine(TCM),the prototype constituents and metabolites were screened out to elucidate the chemical basis of XJC.Based on the mammary gland hyperplasia model rat,the dynamic change of multiple components in vivo was studied to provide scientific basis for clinical drug monitoring.So that Xiaojin Capsule in the clinical will be a greater degree of its efficacy,better for the benefit of mankind.Methods:The chemical constituents of XJC in vivo were characterized by using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry combined with multiple data processing approach in UNIFI~TMM platform.A chemical component database was summarized by searching database and related literature.The chemical component database was imported into UNIFI platform to match the mass spectra of dosed rat serum.The prototype compounds were tentatively characterized by comparing with standard substance and referencing to related literature.On the basis of prototype components,the related metabolites were predicted by the UNIFI platform.(2)To establish a biological analysis method for simultaneous detection of 6 prototype components(aconine,songorine,neoline,AKBA,KBA,2-hexyl-5-ethyl-furan-3-sulfonate)of XJC in rat plasma based on HPLC-MS/MS.(3)Adult female SD rats were selected to establish mammary gland hyperplasia model by injection of estrogen(estradiol benzoate,progesterone).After single oral administration of XJC,blood was collected from the fundus venous plexus at a preset time point.LC-MS/MS method was used to determine the plasma concentrations of six prototype components in rats at different time points.The main pharmacokinetic parameters were calculated by DAS 2.0 software,and the dynamic changes of the main medicinal components of XJC in mammary gland hyperplasia model rats were described.Results:(1)A total of 28 prototype compounds were tentatively characterized by comparing with standard substance and referencing to related literature,including alkaloids,triterpenic acid and furan sulfonic acid.And a total of 29 metabolites were finally identified.The main types of metabolic reactions are deacetylation,dehydration,oxidation,glucuronidation and sulfonation.(2)A rapid,simple,sensitive,stable and reliable HPLC-MS/MS method has been developed for the simultaneous determination of 6 prototype components of XJC in rat plasma.The validated method of biological samples was carried out,specificity,linear range,lower limit of quantitation,precision,accuracy,matrix effect and stability meet the analytical requirements of biological samples.(3)The study found that although the three aconitine alkaloids have similar structures,the pharmacokinetic parameters in the body showed significant differences,and the songorine showed a double peak phenomenon.Both AKBA and KBA are pentacyclic triterpenoids.Compared with AKBA,KBA exhibits faster absorption and elimination rates,but both appear to a double peak phenomenon.This study is the first to characterize the pharmacokinetics of 2-hexyl-5-ethyl-furan-3-sulfonate in rats.It showed a strong response in vivo,reaching a peak concentration at 2.125 h after administration,and a concentration of 0 in vivo after 24 h,showing a double peak phenomenon.Conclusion:In this study,57 kinds of chemical components were identified in rat serum after oral administration of XJC.This work clarified the material basis of XJC and bio-active compounds in vivo.A rat model of mammary gland hyperplasia was established,and the dynamic changes of six prototype components of aconine,songorine,neoline,AKBA,KBA and 2-hexyl-5-ethyl-furan-3-sulfonate in rats were elucidated.This study could provide the experimental data reference for clinical application of XJC.