摘要
目的应用Caco-2细胞模型对卡莫氟(carmofur,1-hexylcarbamoyl-5-fluorouracil,HCFU)的吸收、转运特性及其机制进行研究。方法分别考察时间、pH、浓度及抑制剂对HCFU吸收的影响;测定药物在不同时间双向转运的速度,计算HCFU的表观渗透系数,研究不同药物浓度对其转运的影响。结果Caco-2细胞对HCFU的吸收在20min内呈线性,药物摄取时间定为10min;pH对HCFU的吸收没有显著影响,浓度依赖性结果显示,HCFU的吸收由一个饱和成分和一个非饱和成分组成;P-糖蛋白(P-glycoprotein,P-gp)抑制剂维拉帕米对HCFU的吸收基本没有影响,而耐药相关性蛋白(MRP)抑制剂MK571的存在可显著增加对HCFU的吸收(P<0.05)。双向转运的表观渗透性存在方向性差异,且受浓度的影响。结论HCFU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,MRP2可能对HCFU的吸收有外排作用。
OBJECTIVE To investigate the uptake, transepithelial transport characteristics and the cellular uptake mechanism of carmofur, 1-hexylcarbamoyl-5-fluorouracil（HCFU） in the Caco-2 cells model. METHODS The uptake studies of HCFU were investigated through the time（1, 2, 5, 10, 20 min）, pH （6.5, 7.4） and concentration（0-300 μmol·L^-1） dependence assays. The cellular uptake mechanism of HCFU was determined with the P-gp inhibitor of verapamil and the MRP inhibitor of MK571. The transepithelial transport was measured using Caco-2 cell monolayers grown in Transwell chambers at different time（30, 60, 90, 120 min） and concentrations（25, 100 μmol·L^-1）, and the permeability was calculated. RESULTS The uptake of HCFU in Caco-2 cells showed a linear range in 20 min and the uptake time was fixed at 10 rain. No significant pH-dependent influnce was observed in Caco-2 cells. The concentration-dependent uptake of HCFU consisted of one saturable and one nonsaturable component. Verapamil（100 μmol·L^-1） almost had no effect on the uptake of HCFU, and MK571（50μmol·L^-1） increased the uptake significantly（P〈0.05）. The permeability showed directional different（P〈0.05）, Papp（BL→AP）/Papp（AP→BL） was 1.7 and the Papp（BL→AP）decreased significantly（P〈0.05） with increasing concentration. CONCLUSION The absorption of HCFU in Caco-2 cells model included active and passitive manner, involved in effiux transport, and MRP2 maybe play an important role in the effiux of HCFU in Caco-2 cells.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2009年第21期1637-1642,共6页
Chinese Pharmaceutical Journal
基金
辽宁省自然科学基金资助项目(20082103)
