A new strategy of enhancing absorptivity and safety for evodiamine: polyamidoamine derivatives modified by polyethylene glycol chain  

作　　者：Yao-Chun Gao Yuan-Sheng Lao Meng-Xue Zhang Nan Li Chen-Yang Wu Zheng-Qi Dong 

机构地区：[1]Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100193,China [2]Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine,Ministry of Education,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100094,China [3]Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription,Beijing 100700,China

出　　处：《Traditional Medicine Research》2021年第2期100-110,共11页TMR传统医学研究

基　　金：This research was funded by National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2015ZX09501005);Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2016-I2M-1-012).

摘　　要：Background:Traditional Chinese medicine involves complex ingredients and mixtures of ingredients that often exhibit low bioavailability,and excipients are often lacking to increase the absorption-enhancing effects.This study modified the generation 4 polyamidoamine dendrimer with polyethylene glycol of different molecular weights(5000,2000,1000)to form a series of polyamidoamine-co-polyethylene glycol(PAMAM-co-PEG)as a novel class of oral absorption enhancers.Evodiamine,the major alkaloid found in the traditional Chinese medicine Wu Zhu Yu(Fructus Evodiae),was used as a model drug to verify the absorption-enhancing effects and the safety of this alkaloid.Methods:This study utilized the solubility determination method documented in the Pharmacopoeia of the People’s Republic of China(2015 edition)and the D0 values recommended in the US FDA guidelines to comprehensively evaluate the solubility of evodiamine.The permeability of evodiamine was assessed using the apparent permeability coefficient in experiments based on in vitro cell models.Multiple aspects of the biological safety of PAMAM-co-PEG were explored using the MTT assay,LDH assay,and total protein release of the rat intestinal tract.Moreover,the absorption-enhancing effects of PAMAM-co-PEG at different molecular weights on evodiamine were verified via the use of in vitro cell models and in vivo intestinal loop circulation experiments with rats.Results:Evodiamine exhibited low solubility and permeability and was classified into class IV compounds using the biopharmaceutical classification system.PAMAM-co-PEG 2000 demonstrated improvement in the biosafety and absorption-enhancement effect of evodiamine at a specific concentration.This study showed that 0.05%(w/v)of PAMAM-co-PEG 2000 increased the cumulative penetration of evodiamine via cell transport by 1.32 times,and 0.10%(w/v)of PAMAM-co-PEG 2000 increased the area under curve value of evodiamine by 1.31 times.Conclusion:Evodiamine possesses low solubility and permeability and leads to poor oral bioavaila

关 键 词：Polyamidoamine dendrimers Polyethylene glycol Intestinal absorption enhancer BIOAVAILABILITY EVODIAMINE Fructus Evodiae 

分 类 号：O62[理学—有机化学]