Liu Yixian, Wang Yafeng, Peng Youmei, Liu Bingjie, Ma Fang, Jiang Jinhua, Wang Qingduan, Chang Junbiao
Pharmazie. 2018 Sep 1;73(9):503-507. doi: 10.1691/ph.2018.8555.
The purpose of the present study was to dig into recent studies designed to characterize the impacts of 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) on P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). Specifically, the modulation effects of FNC on P-gp, MRP2 and BCRP protein expressions were assessed by western blot methods. 5 (and 6)-Carboxy-2',7'-dichloroflourescein (CDF) and BODIPY-prazosin were used to provide indications of alterations of MRP2 and BCRP activities. The effects of P-gp, MRP2 and BCRP on FNC were evaluated in the in situ single-pass intestinal perfusion model. The results showed that FNC at higher concentrations and with longer incubation times can upregulate the protein expression of P-gp, MRP2 and BCRP in Caco-2 cells. The upregulated proteins were also functionally active, as revealed by a lower degree of CDF and BODIPY-prazosin uptake by the cell monolayers. The intestinal absorptive coefficient (Peff) was observed to significantly increase with the inhibitors of P-gp, MRP2 and BCRP. These results suggested that FNC could modulate the expressions and functions of P-gp, MRP2 and BCRP, while P-gp, MRP2 and BCRP were involved in the efflux transport of FNC. The inductive effects of FNC on P-gp, MRP2 and BCRP suggested the possibility of FNC to contribute to the inter- and intra-individual variability of itself, as well as to alter the absorption of other drugs that may be administered concomitantly.
本研究的目的是深入探究最近旨在表征2'-脱氧-2'-β-氟-4'-叠氮胞苷（FNC）对P-糖蛋白（P-gp）、多药耐药相关蛋白2（MRP2）和乳腺癌耐药蛋白（BCRP）影响的研究。具体而言，通过蛋白质印迹法评估FNC对P-gp、MRP2和BCRP蛋白表达的调节作用。使用5（和6）-羧基-2'，7'-二氯荧光素（CDF）和BODIPY-哌唑嗪来指示MRP2和BCRP活性的变化。在原位单通道肠道灌注模型中评估P-gp、MRP2和BCRP对FNC的影响。结果表明，较高浓度且孵育时间较长的FNC可上调Caco-2细胞中P-gp、MRP2和BCRP的蛋白表达。上调的蛋白也具有功能活性，这通过细胞单层对CDF和BODIPY-哌唑嗪的摄取程度较低得以揭示。观察到肠道吸收系数（Peff）随着P-gp、MRP2和BCRP的抑制剂而显著增加。这些结果表明，FNC可调节P-gp、MRP2和BCRP的表达和功能，而P-gp、MRP2和BCRP参与FNC的外排转运。FNC对P-gp、MRP2和BCRP的诱导作用表明，FNC有可能导致其自身的个体间和个体内变异性，并改变可能同时给药的其他药物的吸收。
