候选药物TW918在Caco-2细胞模型中的吸收和转运特性  

Absorption and transport characteristics of the candidate drug TW918 in Caco-2 cell model

作　　者：李谦[1] 杨育才[2] 王立强[1] 

机构地区：[1]华侨大学分子药物研究院,泉州362021 [2]台湾大学生化科学系,台北10617

出　　处：《中国新药杂志》2014年第23期2781-2785,2793,共6页Chinese Journal of New Drugs

基　　金：泉州市科技计划重点项目(2013Z35)

摘　　要：目的:研究候选药物TW918在Caco-2细胞模型中的吸收、转运特性及其机制。方法:建立Caco-2细胞摄取、转运模型,采用HPLC法检测Caco-2细胞单层的完整性及P-糖蛋白(P-gp)的功能,测定单层细胞的跨膜电阻(TEER),分别考察时间、p H、浓度及抑制剂对TW918吸收的影响;测定药物在不同转运时间双向转运的速度,计算TW918的表观渗透系数。结果:用于转运实验和摄取实验的Caco-2细胞能形成均匀的细胞单层,且其致密性、完整性及功能性均良好。Caco-2细胞对TW918的吸收在20 min内呈线性关系,药物的摄取时间定为10 min;p H对TW918的吸收没有显著影响,浓度依赖性结果显示,TW918的吸收由一个饱和成分和一个非饱和成分组成;P-gp抑制剂维拉帕米对TW918的吸收无显著影响,而耐药相关性蛋白(MRP)抑制剂MK571可显著增加Caco-2对TW918的吸收(P<0.05)。双向转运的表观渗透性存在方向差异,且受浓度的影响。结论:TW918在Caco-2细胞中以主动和被动2种形式吸收,其吸收存在外排机制,可能是MRP2对TW918的吸收有外排作用。Objective： To investigate the uptake, transepithelial transport characteristics and cellular uptake mechanism of TW918 in the Caco-2 cell model. Methods： The Caco-2 cell model was established and used to study the absorption and transportation of TW918. The monolayer integrity of Caco-2 cells and function of the P-gp were detected by HPLC, and transepithelial resistance （TER） of monolayer ceils was measured. The uptake of TW918 was investigated by the factors including time, pH and concentration. The bidirectional transfer speed of drug at different times was measured and the apparent permeability was calculated. Results： Cell monolayer with the properties of good compactness, integrity, and functionality was formed in both of the uptake and transport tests. The uptake of TW918 in Caco-2 cells showed a linear range in 20 rain and the uptake time was fixed at l0 min. No significant pH-dependent influence was observed in Caco-2 cells. The concentration-dependent uptake of TW918 consisted of one saturable and one nonsaturable component. Verapamil almost had no effect on the uptake of TW918, and MK571 increased the uptake significantly （P 〈0.05）. The permeability showed directional difference （P 〈 0.05 ） , and decreased significantly with increasing of concentration. Conclusion ： The absorption of TW918 in Caco-2 cells includes active and passive manners, and involves in efflux transport; MRP2 maybe play an important role in the efflux of TW918 in Caco-2 cells.

关 键 词：TW918 CACO-2细胞模型 吸收 转运 

分 类 号：R94[医药卫生—药剂学]