A new strategy to rapidly evaluate kinetics of glucuronide efflux by breast cancer resistance protein (BCRP/ABCG2).
A new strategy to rapidly evaluate kinetics of glucuronide efflux by breast cancer resistance protein (BCRP/ABCG2).
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DOI：
10.1007/s11095-012-0817-2
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发表时间：
2012-11
影响因子：
3.7
通讯作者：
Hu, Ming
中科院分区：
文献类型：
--
作者：
Wu, Baojian;Jiang, Wen;Yin, Taijun;Gao, Song;Hu, Ming
外排转运体乳腺癌耐药蛋白(BCRP/ABCG2)在人体内对包括葡萄糖醛酸苷在内的阴离子药物和代谢物的排泄起着重要作用。在本文中，我们最近发表的细胞模型(即HeLa细胞过度表达UGT1A9(HeLa1A9))被用来确定BCRP介导的葡萄糖醛酸苷转运的动力学参数。在糖苷元与细胞孵育后，其葡萄糖醛酸苷的排泄迅速达到并维持稳定状态(即零级或接近零级)。通过改变苷元的浓度，可以获得不同的(细胞内)葡萄糖醛酸苷浓度及其相应排泄率的动力学图谱，从而可以确定导致BCRP介导的葡萄糖醛酸苷外流的动力学参数。这一方法在理论上得到了细胞药代动力学模型的验证，该模型结合了各种酶和转运体介导的动力学过程。实验还证实，在HeLa1A9细胞模型中，6-羟基黄酮酸和4-甲基伯菲酮葡萄糖醛酸苷的外流动力学参数与BCRP高表达膜囊泡的外流动力学参数一致。本研究为快速评价BCRP的葡萄糖醛酸外排动力学提供了一种新的策略。
The efflux transporter breast cancer resistance protein (BCRP/ABCG2) plays an important role in excretion of anionic drugs and metabolites including glucuronides in humans. In this article, our recently published cell model (i.e., HeLa cells over-expressing UGT1A9 (HeLa1A9)) is used to determine the kinetic parameters of BCRP-mediated transport of glucuronides. After incubation of the aglycone with the cells, a steady-state (i.e., zero-order or near zero-order) excretion of its glucuronide is rapidly achieved and then maintained. Kinetic profiling with different (intracellular) glucuronide concentrations and their corresponding excretion rates is enabled by varying the concentration of the aglycone, which allows for the determination of kinetic parameters responsible for BCRP-mediated efflux of glucuronides. This approach was validated theoretically using a cellular pharmacokinetic model incorporating various enzymatic and transporter-mediated kinetic processes. It was also validated experimentally in that kinetic parameters of efflux of glucuronides of 6-hydroxyflavone and 4-methylumberiferone in the HeLa1A9 cell model were shown to be consistent with those derived with BCRP-overexpressing membrane vesicles. This study provides a new strategy for rapidly evaluating the kinetics of glucuronide efflux by BCRP.
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