大鼠稳态脑分布模型评价药物的血脑屏障通透性

发布时间：2018-11-28 12:20

【摘要】：目的建立大鼠稳态脑分布模型用于评价安替比林、阿替洛尔和ZZB系列新药候选化合物的稳态脑分布和血脑屏障通透性。方法大鼠静脉推注负荷剂量的药物后恒量输注使血药浓度达到稳态,取血和脑组织样品,LC-MS/MS定量测定血浆和脑组织药物浓度,计算稳态脑血比值(Kp值)。在Caco-2单层细胞体外模型上评价受试药物的双向跨膜通透性,计算表观通透系数(Papp)。结果安替比林和阿替洛尔分别为已知的血脑屏障易通透和难通透药物。安替比林的平均稳态脑分布浓度为(2561±125)ng/g,Kp值为0.93±0.04。阿替洛尔则分别为(20.1±0.8)ng/g和0.015±0.002。安替比林的Kp值约为阿替洛尔的60倍。ZZB系列化合物的结构相似,但Kp值的差异较大,从0.044到6.41,并与Caco-2细胞模型的Papp值不相关。结论建立的大鼠稳态脑分布模型可快速形成稳态血浆浓度,适用于药物血脑屏障通透程度的评价,方法简单、可靠且经济。
[Abstract]:Objective to establish a rat model of steady-state brain distribution to evaluate the steady-state brain distribution and blood-brain barrier permeability of antipyrine, atenolol and ZZB series of new drug candidates. Methods the plasma and brain tissue samples were collected and the plasma and brain tissue concentrations were measured quantitatively by LC-MS/MS, and the steady-state cerebral blood ratio (Kp) was calculated. Two-way transmembrane permeability of tested drugs was evaluated on Caco-2 monolayer cell model in vitro, and apparent permeability coefficient (Papp).) was calculated. Results Antipyrine and atenolol were known as blood-brain barrier permeable drugs. The mean steady-state brain concentration of antipyrine was (2561 卤125) ng/g,Kp (0.93 卤0.04). Atenolol was (20.1 卤0. 8) ng/g and 0.015 卤0. 002, respectively. The Kp value of antipyrine was about 60 times of that of atenolol. The structure of ZZB series was similar, but the Kp value varied from 0.044 to 6.41, which was not related to the Papp value of Caco-2 cell model. Conclusion the established rat model of steady brain distribution can rapidly form stable plasma concentration, which is suitable for evaluating the permeability of blood-brain barrier. The method is simple, reliable and economical.
【作者单位】：抗毒药物和毒理学国家重点实验室军事医学科学院毒物药物研究所;
【基金】：国家“重大新药创制”科技重大专项资助项目(2015ZX09J15104) 全军医学科研“十二五”重大项目(AWS11C004)
【分类号】：R965

【参考文献】