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 20 min 内呈线性，药物摄取时间定为 10 min ； 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。
Abstract
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 mmol·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 mmol·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 min. 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 mmol·L-1) almost had no effect on the uptake of HCFU, and MK571(50 mmol·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 efflux transport， and MRP2 maybe play an important role in the efflux of HCFU in Caco-2 cells.
关键词
卡莫氟 /
Caco-2 细胞模型 /
吸收 /
转运
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Key words
carmofur /
Caco-2 cells model
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参考文献
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（ 收稿日期 ： 2009-02-17 ）
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