Studies on the intestinal absorption characteristics of sulfasalazine, a breast cancer resistance protein (BCRP) substrate.
Studies on the intestinal absorption characteristics of sulfasalazine, a breast cancer resistance protein (BCRP) substrate.
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DOI：
10.2133/dmpk.dmpk-12-nt-024
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发表时间：
2013
影响因子：
2.1
通讯作者：
Atsuko Tomaru;Nozomi Morimoto;M. Morishita;K. Takayama;T. Fujita;K. Maeda;H. Kusuhara;Y. Sugiyama
中科院分区：
文献类型：
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作者：
Atsuko Tomaru;Nozomi Morimoto;M. Morishita;K. Takayama;T. Fujita;K. Maeda;H. Kusuhara;Y. Sugiyama
口服柳氮磺吡啶(SASP)现在临床上被用作乳腺癌耐药蛋白(BCRP)活性的探针底物，但SASP的肠道吸收特性尚不清楚。本研究旨在阐明SASP在小鼠肠道的转运特性。在没有或存在BCRP抑制剂Ko134的情况下，外翻回肠与SASP孵育。在没有K134的情况下，稳态的肠道吸收清除量为0.14微米L/分钟/厘米，在有K134的情况下增加了4.8倍。这些结果表明，BCRP介导了SASP在肠道中的外流。在0.1~50µM范围内，SASP在野生型小鼠体内的吸收清除量没有浓度依赖关系。相反，在KO134存在下，SASP的吸收清除率显著降低，且呈浓度依赖关系。在BCRP(-/-)小鼠身上也得到了类似的结果。这些结果提示某些内流转运体可能参与了SASP的肠道吸收。综上所述，SASP的肠道吸收中既有流入转运体，也有流出转运体，这可以解释为什么不同浓度的SASP对野生型小鼠的吸收清除率没有发生变化。
Oral sulfasalazine (SASP) is now used clinically as a probe substrate of a breast cancer resistance protein (BCRP) activity; however the intestinal absorption characteristics of SASP are not well understood. The purpose of this study was to clarify the characteristics of SASP transport in the mouse intestine. The everted ileum was incubated with SASP in the absence or presence of the Bcrp inhibitor Ko134. The steady-state intestinal absorptive clearance was 0.14 µL/min/cm in the absence of Ko134 and increased by 4.8-fold in the presence of Ko134. These results indicate that Bcrp mediates the efflux of SASP in the intestine. The absorptive clearance of SASP did not change in a concentration-dependent manner in the range of 0.1 to 50 µM in wild-type mice. By contrast, the absorptive clearance of SASP decreased significantly in a concentration-dependent manner in the presence of Ko134. Similar results were obtained in Bcrp(-/-) mice. These results suggest the possible involvement of some influx transporters in the intestinal absorption of SASP. In conclusion, both the influx and efflux transporters are involved in the intestinal absorption of SASP, which would explain why the absorptive clearance did not appear to change at various SASP concentrations in wild-type mice.