基于肠道PEPT1转运体的口服高效环糊精包合物的构建及转运机制研究

Oral administration was the dominant dosing route for the patient. But, at present, more emphasis has been placed on the affinity of new chemical entities to the target receptor during the process of drug development, which lead to the unsuitability for some drugs to oral administration because of the undesirable pharmacokinetic characteristics. The intestinal membrane transporters widely.expressed in th organism have become promising targets for oral drug delvery.Cyclodextrin because of cheap, good biocompatibility and has been widely applied to improve the bioavailability and stability of the drug.This topic selection of intestinal oligopeptide transporters (PEPT1) as the target, in beta - cyclodextrin hydroxyl in turn introduce butanediol connection arm and amino acids, and the inclusion of BCS IV drugs of curcumin, the preparation of the curcumin PEPT1 targeted entrapped cyclodextrin complex, such as X ray diffraction method to identify clathrate clathrate and PEPT1 affinity and drug inclusion rate, stability, water soluble, dissolution of examining clathrate and filter parameters, such as;In rats and dogs in vivo pharmacokinetic study the pharmacokinetic behavior of drugs, ultimately selected the best PEPT1 targeted entrapped cyclodextrin complex.Research for PEPT1 as targets for new entrapped cyclodextrin complex design, solve the scientific problem of poor drug oral absorption provides a new model.

口服给药是药物首选给药途径，但目前对候选药物的体外筛选普遍仅注重药物与作用靶点的亲和性，这常导致获得的药物不适合口服给药。分子生物学的发展揭示了肠道黏膜中表达有多种药物转运蛋白，其在药物的肠吸收和分泌过程中扮演重要角色，以其为靶点提高药物的口服吸收越来越受到人们关注。环糊精因价廉易得、生物相容性好而被广泛用于提高药物的生物利用度和稳定性。课题选用肠寡肽转运蛋白(PEPT1)为靶点，在β-环糊精羟基位依次引入丁二醇连接臂和氨基酸，并对BCSIV类药物姜黄素进行包合，制备了姜黄素的PEPT1靶向环糊精包合物，以X射线衍射法等对包合物进行鉴别，以包合物与PEPT1的亲和性及药物的包合率、稳定性、水溶性等参数对包合物进行考察和筛选；以大鼠及犬体内药动学考察药物的药动学行为，最终筛选出最佳PEPT1靶向环糊精包合物。研究为以PEPT1为靶点设计新型环糊精包合物，解决药物口服吸收差的科学难题提供了借鉴

口服给药是药物首选的给药途径，但目前对候选药物的体外筛选普遍仅注重药物与作用靶点的亲和性，而忽视了药物自身的药动学属性，这常导致获得的药物因溶解度低、不易跨膜吸收而不适合口服给药。课题以肠寡肽转运蛋白(PEPT1)为靶点，设计并制备了新型口服PEPT1靶向环糊精包合物，以同时提高药物的水溶性、膜渗透性及稳定性。研究首先合成了PEPT1靶向环糊精衍生物，并制备了姜黄素PEPT1靶向环糊精包合物。以X射线衍射法等多种手段对包合物进行了表征，同时也对姜黄素PEPT1靶向环糊精包合物的水中溶解度及稳定性进行了考察。在此基础上，建立了PEPT1高表达Caco-2细胞模型，对靶向包合物的细胞摄取、PEPT1对底物立体结构的选择性、PEPT1底物对靶向包合物摄取的竞争性抑制、靶向包合物的跨膜摄取及肠绒毛吸收进行了研究。最后，对靶向包合物进行了口服药物动力学方面的研究。研究结果表明，与游离姜黄素相比，姜黄素PEPT1靶向环糊精包合物的口服吸收提高了5.39倍。研究为改善姜黄素的口服生物利用度，同时也为其他难溶性药物口服给药系统的开发提供了新的设计思路与借鉴。