Pharmacokinetics Of Rheum Palmatum Rhizome And Roots(Dahuang)After Dosing Lianhua Qingwen Capsule

Objective: Lianhua Qingwen capsule is a representative treatment drug for respiratory diseases,which is guided by“Collateral Disease”theory.In COVID-19,Lianhua Qingwen is mainly used to improve the symptoms of fever,fatigue,cough and gastrointestinal discomfort in patients during medical observation period.This investigation focused on the Rheum palmatum rhizome and roots(Dahuang).Serial pharmacokinetic investigations reported that the main systemic exposure to compounds in rat after receiving rhubarb extract or related preparations contains chrysophanol,emodin,rhein,aloe-emodin and physcion.However,only rhein was detected in human body.At present,the mechanism of species difference is not clear.In addition,based on the complexity of herb combinations,little is known about the chemical basis of the medicines’ therapeutic actions and adverse reactions of Lianhua Qingwen.The aim of this study was to identify Dahuang compounds,that are likely to be therapeutically important,after oral administration of Lianhua Qingwen,and compare the similarities and differences between human and rats.Methods:Based on the analysis of chemical composition and quality consistency of Dahuang in Lianhua Qingwen,the pharmacokinetics were studied in vivo and in vitro between human and rats.All samples were analyzed by LC-MS/MS or UPLC/TOF-MS.Based on the chemical composition,systemic exposure to compounds and various in vitro studies,this study reveal the potential therapeutical compounds and compare the similarities and differences between human and rats.Results: A total of 56 constituents,originating from the component Dahuang,were detected and characterized in samples of Lianhua Qingwen.Chrysophanol,chrysophanol-8-O-glucoside,emodin,rhein,rhein-8-O-glucoside,methyl-rhein and gallic acid were the major Dahuang compounds.Rhein,methyl-rhein,3-O-methylgallic acid and4-O-methylgallic acid were the main systemic exposure to compounds in volunteers after receiving Lianhua Qingwen.Rats were similar to volunteers,but the difference was that chrysophanol and gallic acid were also significantly exposure to in rats.Rhein and methyl-rhein were predominantly excreted by kidney in the form of unchanged.Gallic acid was predominantly excreted by kidney and feces in the form of unchanged and metabolic.Chrysophanol,the major Dahuang constituent in Lianhua Qingwen,was not systemic exposure to in volunteers because of poor intestinal absorption and predominantly excreted by feces.However,it was predominantly excreted by kidney and bile in rats in the form of unchanged and metabolic.The absorbed anthraquinones aglycone can be metabolized in liver by UGTs.Anthraquinone glycoside can be hydrolyzed by β-glucosidase and colonic microbiota,which can increase the systemic exposure to anthraquinones aglycone.The significant systemic exposure to rhein associated with its membrane permeability,and the metabolites of main exposure to compounds in human and rats were identified by in vitro study.Anthraquinone glycosides mainly occurred glucuronidation and hydroxylation metabolism,and gallic acid mainly occurred methylation metabolism.Conclusion: To our knowledge,the human pharmacokinetic data originating from Dahuang of Lianhua Qingwen are reported here for the first time.After administration of Lianhua Qingwen,the pharmacokinetic characteristics of main exposure to compounds were species similarities between human and rats except for the chrysophanol and gallic acid.This investigation,together with such investigations for the other component herbs,facilitates better defining therapeutic benefit of Lianhua Qingwen and conditions for its safe use.