P-糖蛋白对番荔枝酰胺衍生物FLZ在Caco-2细胞模型中跨膜转运的影响

中国药物警戒 ›› 2015, Vol. 12 ›› Issue (2): 69-72.

P-糖蛋白对番荔枝酰胺衍生物FLZ在Caco-2细胞模型中跨膜转运的影响

刘潜¹，²,陈晓光¹,侯金凤¹,张金兰¹,陈辉¹,张丹¹,鲍秀琦¹,孙华¹*

1中国医学科学院药物研究所，北京 100050;
2北京市神经外科研究所，北京 100050

收稿日期:2015-01-15 出版日期:2015-02-08 发布日期:2015-07-28
通讯作者: 孙华女，博士，副研究员，硕士研究生导师，肝脏生化药理学及肿瘤多药耐药性。
作者简介:刘潜，女，博士，中枢神经系统肿瘤及分子药理研究。

Effect of P-glycoproteinon on the Permeability of Squamosamide Derivative FLZ across Caco-2 monolayer Model

LIU Qian¹,²，CHEN Xiao-guang¹，HOU Jin-feng¹，ZHANG Jin-lan¹，CHEN Hui¹，ZHANG Dan¹，BAO Xiu-qi¹，UN Hua¹*

1Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2Beijing Neurosurgical Institute, Capital Medical University, Beijing, China, 100050

Received:2015-01-15 Online:2015-02-08 Published:2015-07-28

摘要/Abstract

摘要： 目的考察转运蛋白P-糖蛋白（P-glycoprotein，P-gp）对番荔枝酰胺衍生物FLZ体外跨血脑屏障（Blood-brain barrier，BBB）转运的影响。方法采用体外培养的Caco-2细胞建立体外BBB模型，研究1, 5, 10 μM FLZ跨膜转运特性。并探讨加入P-gp抑制剂5 μM zosuquidar后FLZ跨膜转运的表观渗透系数和外排率的变化。结果 FLZ在Caco-2细胞模型上显示出了极性转运特性，Papp（B~A）> Papp（A~B），并呈现出良好的剂量依赖关系。同时FLZ在Caco-2细胞的跨膜转运中也呈现外排现象，1, 5, 10 μM FLZ的外排率ER值分别为2.56，3.67和5.06。P-gp抑制剂zosuquidar可以显著降低FLZ外排，增加转运。10 μM FLZ的外排率由5.06降低为1.94，下降了2.6倍。结论 FLZ具有P-gp的底物特性，P-gp参与了FLZ在BBB跨膜转运中的外排。

关键词: P-糖蛋白, FLZ, 血脑屏障, Caco-2

Abstract: Objective To study the effect of P-glycoprotein (P-gp) on the transport characteristics of squamosamide derivative FLZ across in vitro blood-brain barrier (BBB) model. Methods A human intestinal epithelial cell Caco-2 in vitro BBB model was applied to study the transport characteristics of 1, 5, 10 μM FLZ．The effects of P-gp inhibitor zosuquidar on the in vitro permeability and efflux ratio of FLZ were also investigated. Results The transport of various concentrations of FLZ (1, 5, 10 μM) through the Caco-2 model occurred in both A~B and B~A directions, and Papp B~A transport were significantly higher than those for A~B transport at each FLZ concentration. The efflux ratio of 1, 5, 10 μM FLZ was 2.56, 3.67 and 5.06, respectively, suggesting the presence of efflux pumps to remove FLZ from within cell membranes. Upon specific blocking of P-gp using zosuquidar increased intracellular accumulation of FLZ in Caco-2 model and significantly reduced the efflux ratio from 5.06 to 1.94. Conclusion FLZ is a substrate for the P-gp drug efflux transporter, and poor brain penetration of FLZ is mainly due to the P-gp transport system in the BBB.

Key words: P-glycoprotein, FLZ, blood-brain barrier, Caco-2

中图分类号:

R965
R971.5

刘潜,陈晓光,侯金凤,张金兰,陈辉,张丹,鲍秀琦,孙华. P-糖蛋白对番荔枝酰胺衍生物FLZ在Caco-2细胞模型中跨膜转运的影响[J]. 中国药物警戒, 2015, 12(2): 69-72.

LIU Qian,CHEN Xiao-guang，HOU Jin-feng，ZHANG Jin-lan，CHEN Hui，ZHANG Dan，BAO Xiu-qi，UN Hua. Effect of P-glycoproteinon on the Permeability of Squamosamide Derivative FLZ across Caco-2 monolayer Model[J]. Chinese Journal of Pharmacovigilance, 2015, 12(2): 69-72.

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