Metabolites Profile Analysis And Pharmacokinetic Study Of PSORALEAE FRUCTUS,a Traditional Chinese Medicine,in Rats

PSORALEAE FRUCTUS,the mature and dry fruit of Psoralea corylifolia L.,has been used in China for thousands of years.PSORALEAE FRUCTUS was widely used as anti-osteoporosis medicine and was presented in Chinese traditional medicine prescription,such as Xian-ling-gu-bao prescription.Prophase research work have been found that many ingredients of PSORALEAE FRUCTUS could be absorbed into the blood.In order to further elucidate the in vivo efficacy material of PSORALEAE FRUCTUS,metabolites profile of PSORALEAE FRUCTUS and pharmacokinetic study of multiple bioactive constituents in rat plasma were systematically investigated by using UPLC-MS technique.Based on a "representative constitutes based xenobiotics identification" strategy,a total of 142 PSORALEAE FRUCTUS-related xenobiotics were identified or tentatively characterized in rat plasma,biles,urine and feces after oral administration of six representative single compounds and PSORALEAE FRUCTUS extract by UPLC/Q-TOF-MS.All six different types of constituents,including furocoumarin,coumestan,isoflavone,flavanone,chalcone and monoterpene phenol,could be absorbed into the circulation system.Hydration,epoxidation,cyclization,oxidization,reduction,sulfation and glucuronidation were the major metabolic reactions in rats.Bakuchiol,the main active component of PSORALEAE FRUCTUS,showed a range of significant pharmacological.After oral administration of bakuchiol,12 metabolites,including 11 new compounds,were isolated from the urine and feces,and their structures were elucidated by extensive spectroscopic analysis.Based on the metabolites,possible metabolic pathways of bakuchiol in rats were proposed and a rare bile acid conjugation reaction was found.In addition,in vitro test showed that bakuchiol exerted significant effects on ALP activity of MC3T3-E1 cells and cytotoxicity on HKC-8 cells,while B1-B3 only showed almost no ALP activities on MC3T3-E1 cells and no cytotoxicity on HKC-8 cells.An UPLC-MS/MS assay for simultaneous determination of psoralen,psoralidin,bavachin,neobavaisoflavone,isobavachalcone,bakuchiol and norbakuchinic acid,the main metabolite of bakuchiol,in rat plasma was developed.The method was applied to investigate the comparative pharmacokinetics of analytes in rats after oral administration of bakuchiol,a multi-compound mixture of six representative compounds and PSORALEAE FRUCTUS extract.By analysis and comparison,the data indicated that synergistic effect occurred and it led to different bioavailability and pharmacokinetic behaviors of analytes.Meanwhile,a semi-quantitative determination method was applied to charactering the kinetic feature of 16 constituents or metabolites in order to comprehensive illustrating dynamic change process of PSORALEAE FRUCTUS.In summary,these outcomes may reveal the in vivo bioactive material basis of PSORALEAE FRUCTUS to some extent.Addtionally,it also contribute to further study on pharmacodynamics and quality control.