5-氟尿嘧啶与卡莫氟的理化特性对其渗透性的影响

Effect of Physicochemical Characteristics on the Permeability of 5-fluorouracil and Carmofur

目的应用Caco-2细胞模型研究5-氟尿嘧啶(5-fluorouracil,5-FU)和卡莫氟(carmofur,HCFU)的渗透性并探讨物理化学性质如logP、pKa值、分子量及水溶性等对两者渗透性的影响。方法实验中应用的5-氟尿嘧啶和卡莫氟的pKa值、水溶性等由文献获得,logP值用HyperChem V5.0软件中的ChemPlus模块计算得到;用跨膜电阻值(transepithelial electricalresistance,TEER)和荧光黄检测细胞完整性,进行渗透实验,计算表观渗透系数(apparent permeability coefficients,P_(app))。结果 5-氟尿嘧啶和卡莫氟的logP值分别为-0.96和2.63;细胞的TEER值维持在760～965 Ω·cm^(-2)之间;荧光黄的P_(app)值为(1.89±0.78)×10^(-7) cm·s^(-1),细胞融合形成了连续的单层细胞膜,且其紧密性和完整性良好;HCFU的P_(app)值约是5-FU的P_(app)值的10倍。结论 logP值对5-氟尿嘧啶和卡莫氟在Caco-2细胞模型中的渗透性起决定作用,5-氟尿嘧啶和卡莫氟的理化特性对两者的渗透性有不同的影响。

OBJECTIVE To investigate the permeability of 5-fluorouracil and carrnofur on Caco-2 cell monolayers and the influence of their physicochemical characteristics such as logP, pKa, molecular weight and aqueous solubility on their permeability was determined. METHODS The information of pKa, aqueous solubility etc. was got from the references; logP values was predicted by the ChemPlus modules in the software of HyperChem V5.0; the integrity of Caco-2 cell monolayers was examined by the TEER values and the permeability of Lucifer yellow, performed the permeability assay, calculated the apparent permeability coefficients （Papp）. RESULTS The logP of 5-fluorouracil and Carmofur were 0.96 and 2.63, respectively, the TEER values was in range of 760-965 Ω.cm^-2, the Papp of Lucifer yellow was （1.89±0.78） × 10.7 cm.s^-1, and confluent cell monolayers in tight-junction integrity have formed, the Papp value of Carmofur is 10 folds of 5-fluorouracil. CONCLUSION logP played a decisive role in the permeability on the Caco-2 cell monolayers, and physicochemical characteristics of 5-fluorouracil and carmofur influenced their permeability differently.