Pharmacokinetic Study Of Bioactive Components Of Inulae Radix For Irritable Bowel Syndrome

Irritable bowel syndrome(IBS)is a common functional bowel disorder,which has become disease only less than the cold diseases.IBS has been recognized as a class of special physiological basis of psychosomatic diseases in recent years,involving the gastrointestinal tract motility disorders,visceral hypersensitivity,infections,imbalance of flora and many other factors.Some clinical drugs can only alleviate the symptoms for corresponding effective and have significant side effects.Traditional Chinese medicine has shown good efficacy in IBS.Therefore,therapeutic drug development from commonly used traditional Chinese medicine for IBS is a realistic and useful work of great significance.Inulae Radix,Chinese name “TUMUXIANG,is the root of Inula helenium L.which belongs to the genus Inula(Compositae).It is listed in the Chinese Pharmacopoeia(2015 edition).We found Inulae Radix extract could significantly improved gastrointestinal motility,pharmacodynamics study showed that Inulae Radix lactones had a therapeutic effect on IBS,and the mechanism may be the improvement effevt on the structure of intestinal flora in vivo.Meanwhile,the acute toxicity studies have shown safe profile of the sesquiterpene lactones.Inulae Radix extract is expected to be developed into the first sesquiterpene lactones drug for the treatment of IBS in the world.It is necessary to learn more about the pharmacokinetic parameters of Inulae Radix lactones.UPLC-QTOF/MS method was used for the study on chemical constituents of Inulae Radix.Then,a sensitive and rapid ultraperformance liquid chromatography tandem mass spectrometry method was developed for determination of the two compounds in rat plasma.This method was used to compare the pharmacokinetic characteristics of isoalantolactone and alantolactone in Sprague-Dawley rats by intravenous and oral administration.The results showed low bioavailability of the two lactones,with strong first pass effect and wide tissue distribution,there was some enrichment in the liver and gastrointestinal.The main route of excretion was through bile and feces.Moreover,UPLC-QTOF/MS method was used in the metabolism study in plasma,urine,feces and bile samples.Cysteine binding was the main form of metabolism with some oxidation and dehydrogenation product about isoalantolactone and alantolactone in feces and bile samples.No metabolites were found in plasma and urine samples.It was shown that a combination of metabolism of cysteine binding and ultimately excreted in the bile and feces lead to low bioavailability in vivo.Caco-2 cell model was used to investigate the intestina absorption of alantolactone and isoalantolactone.It was found that the high absorption permeability of both lactones with passive diffusion,active efflux MRP and BCRP-mediated diffusion were the absorption mechanism of the two lactones.Artificial gastric juice,simulated intestinal fluid,intestinal bacteria from rat and liver microsomes model were used for evaluation of metabolism about alantolactone and isoalantolactone in vitro.No metabolites were found in artificial gastric juice,simulated intestinal fluid and intestinal bacteria.Strong metabolic reactions were found in the liver microsomes model and the the main metabolic form was cysteine binding.The study about pharmacokinetic of alantolactone and isoalantolactone is useful for the druggability study about Inulae Radix extract for irritable bowel syndrome.It confirms that first pass effect of liver is the main reason of low bioavailability of the two isomers in rats after oral administration of Inulae Radix excract.Consider its binding target,Inulae Radix extract could be a potential new drug to treat IBS.