人酸性成纤维细胞生长因子与穿膜肽融合蛋白在鼠体内的药代动力学及血脑屏障通透性研究.docVIP

· 1204 · 药学学报 Acta Pharmaceutica Sinica 2011, 46 (10): 1204?1208 人酸性成纤维细胞生长因子与穿膜肽融合蛋白在鼠体内的 药代动力学及血脑屏障通透性研究 杨鹏辉1, 许 华1, 张齐好2, 李 娟1, 熊耀玲1, 黄亚东2, 苏志坚2, 郑 青1* (暨南大学 1. 药学院, 2. 医药生物技术研究开发中心, 广东 广州 510632) 摘要: 研究穿膜肽 (transcriptional activator protein, TAT) 和人酸性成纤维细胞生长因子 (human acidic fibroblast growth factor, haFGF) 融合蛋白TAT-haFGF14?154静脉注射 (iv) 后在大鼠血浆中的药代动力学特性, 并 探讨其在大鼠和小鼠体内血脑屏障的通透性, 为阿尔茨海默症 (Alzheimer’s disease, AD) 的临床治疗用药提供 依据。酶联免疫吸附实验 (ELISA) 检测静脉注射后TAT-haFGF14?154在大鼠血浆和小鼠脑匀浆液的含量, 免疫 组织化学法检测大鼠和小鼠脑中的分布。结果表明, 大鼠单次颈静脉注射TAT-haFGF14?154 300 μg·kg?1后, 血药 浓度-时间曲线符合二室开放模型, 加权为1/C2, 属于线性动力学消除, 其中, 分布半衰期为 (0.049 ± 0.03) h, 消 除半衰期为 (0.55 ± 0.05) h。结果提示, TAT-haFGF14?154在体内消除较快, 可以迅速穿过血脑屏障, 分布于大脑 皮质和海马区, 并定位于细胞核。 关键词: 穿膜肽; 血脑屏障; 药代动力学; 酸性成纤维细胞生长因子; 阿尔茨海默症 中图分类号: R969.1 文献标识码: A 文章编号: 0513-4870 (2011) 10-1204-05 Pharmacokinetics of a fusion protein for human acidic fibroblast growth factor and transcriptional activator protein in rat and its penetration across blood-brain barrier YANG Peng-hui1, XU Hua1, ZHANG Qi-hao2, LI Juan1, XIONG Yao-ling1, HUANG Ya-dong2, SU Zhi-jian2, ZHENG Qing1* (1. College of Pharmacy, 2. Biopharmaceutical Research and Development Center, Jinan University, Guangzhou 510632, China) Abstract: This paper is to report the study of the pharmacokinetics of a fusion protein TAT-haFGF14?154 for human acidic fibroblast growth factor and transcriptional activator protein in rat plasma, and the investigation of their penetration across blood-brain barrier in mice and rats, in order to provide a basis for clinical development and treatment of Alzheimer’s disease. Enzyme-linked immunosorbent assay (ELISA) was used to determine concentration of TAT-haFGF14?154 in rat plasma and in mouse brain homogenate; and immunohistochemistry was used to analyze the distribution in brain. The concentration-time curve fitted two-compartment open model which was linear kinetics elimination after a single intravenous injection of TAT-haFGF14?154 in rat at the dose of 300 μg·kg?1. The h