Study On Absorption And Interaction Of Multicomponent Drugs And Development Of Combined Intestinal Absorption Platform

Oral administration is one of the main routes for drug delivery.Drugs can only work if they are absorbed.The rate and extent of absorption in the small intestine is very important for the drug’s efficacy.Current research focuses on the pharmacological effects and mechanisms of drugs and often neglects the study of the initial absorption properties of drugs.In addition,the study of the material basis of Traditional Chinese Medicine(TCM)is one of the difficulties for the research and development of new drugs of TCM because of the complexity of their components and the possible interactions in vivo.Multicomponent drugs are becoming more and more common,which have some advantages,such as enhanced efficacy and reduced side effects.Due to the possible interactions between drugs,inappropriate compounding may be harmful and even life-threatening.The study of the absorption of multicomponent drugs and drug interactions during absorption can help the research of the material basis of drugs,drug interaction mechanism and new drug development,etc.Around the above content,the research content of this thesis mainly includes six parts:Chapter 1: Firstly,the drug intestinal absorption and the research status study of in vitro intestinal absorption models were introduced.Secondly,it presents the effects of drug-drug and drug-food interactions on drug intestinal absorption were reviewed.Finally,the current status of research on solid phase extraction technique,solid phase extraction coupled high performance liquid chromatography(HPLC)technique and its use for drug intestinal absorption are presented.Chapter 2: Three in vitro absorption models,including the everted rat gut sac model,the Ussing chamber model and the Caco-2 cell model,were established to screen the potential active ingredients of TCM and compared with the animal model.The Ussing chamber model was found to have the highest agreement with the animal model.Therefore,the Ussing chamber model was selected to screen the potential active components of ten TCMs.A total of 56 potential active ingredients were screened out of 95 ingredients.The Ussing chamber model was used throughout the paper and as a in vitro intestinal absorption model for subsequent experiments.Chapter 3: A UPLC-QE-MS/MS method was developed for the analysis of Yupingfeng granules(YPFG),115 components were obtained and 29 of them were identified.Then,the absorption study of YPFG was conducted using the Ussing chamber model and the results were basically consistent with the animal model.Finally,a quantitative method by detecting 8 main ingredients of YPFG in plasma sample was established to evaluate their pharmacokinetic characteristics and the effect of different types of food on the absorption of YPFG.It was found that alcohol,milk,orange juice and fats had some effects on the intestinal absorption of YPFG.This study provides some theoretical guidance for the clinical use of YPFG.Chapter 4: Firstly,the Ussing model was used to investigate the absorption of four major components in PPAHG,among which acetaminophen(AP)and caffeine(CAF)belong to passive transport,while amantadine(AMA)and Chlorpheniramine(CPA)involve active transport.Then,the effect of the interaction of the components on the intestinal absorption of the components was investigated.Finally,control experiments were designed to confirm that AMA is not a substrate of P-glycoprotein(P-gp),while CPA is a substrate of P-gp.Chapter 5: The Ussing-SPE-HPLC online system for screening and analyzing the potential active components of TCM were established.The animal model and the offline Ussing chamber model were also studied to verify the accuracy and reliability of the online platform.Compared with the offline Ussing chamber model,the online platform could screen potential active ingredients from TCM more effectively and comprehensively with the results of animal model as the control.Chapter 6: It is the summary and outlook.Firstly,the preliminary screening of potential active components of TCM by in vitro intestinal absorption models was established.Next,the study of intestinal absorption of TCM compound and the influence of drug-food interaction on intestinal absorption of medicine were performed.Then,the study of intestinal absorption of compounded drugs and the effect of component interactions on the intestinal absorption of each component were invested.Finally,Ussing-SPE-HPLC online platform was triumphantly established to realize the high-throughput screening of potential active ingredients of TCM.Since the life span of isolated intestine is limited and individual differences are large,the development of a novel intestinal absorption model with complete absorption function,small individual differences,short cycle,long life span and easy availability is very important.