项目名称: 基于血脑屏障转运-生理药动学模型阐明中药生物碱脑部吸收机制并预测其在人体脑内分布
项目编号: No.81202989
项目类型: 青年科学基金项目
立项/批准年度: 2013
项目学科: 医学八处
项目作者: 吴春勇
作者单位: 中国药科大学
项目金额: 24万元
中文摘要: 中药生物碱被广泛用于治疗脑部疾病,而血脑屏障(BBB)上的转运蛋白是影响药物脑部有效性的关键因素。本课题组与日本东京大学合作,建立了BBB网络技术与预测平台,前期发现多个中药生物碱是吡拉明转运蛋白及P-糖蛋白的底物。课题组将继续深入研究,以永生化人脑微血管内皮细胞、转运蛋白过度表达的细胞、野生型和基因敲除小鼠等为研究对象,采用细胞摄取、细胞单层跨膜转运、siRNA转染、小鼠静脉输注、原位脑灌流和脑部微透析等技术,探讨(1)BBB摄取及外排转运蛋白影响生物碱跨BBB的作用机制;(2)收集in silico、in vitro及in vivo特征数据,并引入主动转运过程,以完善生理药动学(PBPK)模型;(3)进行小鼠药动学和组织分布研究以修正模型,预测生物碱在人体脑内的分布。课题不仅能阐明含生物碱成分中药的BBB屏障特征,并为PBPK模型用于中药分子药动学的研究提供新思路和国际合作平台。
中文关键词: 血脑屏障;转运蛋白;石杉碱甲;苦参碱;钩藤碱
英文摘要: A number of alkaloids from Chinese Materia Medica have been used for the treatment of brain diseases. The transporters on the blood-brain barrier (BBB) have been proved to affect the efficacy of many drugs in the brain. Through the collaboration with the University of Tokyo, we have developed good methodologies for the BBB research. Our preliminary experiments demonstrate that severl alkaloids are the substrates of pyrilamine transporter and P-glycoprotein. In this project, several alkaloids will be employed as the model compounds. The transport of model compounds will be investigated in hCMEC/D3 cells and transporter-expressing cells. The contribution of transporters will be determined on mice by various techniques, such as iv infusion, brain in situ perfusion and brain microdialysis. The present research aims to 1) find out the involved transporters for the BBB transport of the model compounds and determine their contributions; 2) collect in silico, in vitro and in vivo data, which will be further analyzed by a hybrid brain PBPK model; 3) perform the mice pharmacokinetics and tissue distribution research to validate and modify the PBPK model and, then predict the human brain distribution of model compounds. Our research will characterize the BBB transport of herbs containing alkaloids, and be greatly helpful f
英文关键词: blood-brain barrier;transporter;huperzine A;matrine;rhynchophylline