Ishida Kazuya, Takaai Mari, Yotsutani Ayano, Taguchi Masato, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
Biol Pharm Bull. 2009 Apr;32(4):741-5. doi: 10.1248/bpb.32.741.
The aim of the present study was to characterize membrane transport mechanisms of mizoribine in the intestinal epithelial cells. We evaluated the contribution of Na(+)-dependent and -independent membrane transporters to mizoribine absorption in the rat intestine using an in situ closed loop method. In addition, we evaluated the effects of structurally related compounds, extracellular Na(+) concentrations, and an inhibitor of Na(+)-independent equilibrative nucleoside transporter, nitrobenzylmercaptopurine ribonucleoside (NBMPR), on the uptake of mizoribine in human intestinal epithelial LS180 cells. In the presence and also absence of Na(+) in rat intestinal loops, more than 60% of the administered dose (50 microg at the concentration of 100 microg/ml=386 microM) of mizoribine was absorbed in 40 min. In the LS180 cells, ribavirin and inosine reduced the uptake of 400 microM mizoribine with the increasing concentrations (from 5 to 50 mM) of the inhibitors. The cellular uptake of mizoribine in the absence of extracellular Na(+) decreased to 72.7% of the uptake in the presence of extracellular Na(+), whereas 100 microM NBMPR decreased the uptake of mizoribine markedly to 34.7% of that without NBMPR. These findings suggest that Na(+)-independent nucleoside transporters are largely responsible for absorption of mizoribine in the intestine.
本研究的目的是表征咪唑立宾在肠上皮细胞中的膜转运机制。我们使用原位闭环法评估了钠依赖性和非依赖性膜转运蛋白对大鼠肠道中咪唑立宾吸收的贡献。此外，我们评估了结构相关化合物、细胞外钠浓度以及非钠依赖性平衡核苷转运蛋白抑制剂硝基苄基巯基嘌呤核糖核苷（NBMPR）对人肠上皮LS180细胞中咪唑立宾摄取的影响。在大鼠肠袢存在和不存在钠的情况下，给药剂量（浓度为100μg/ml = 386μM时为50μg）的咪唑立宾在40分钟内吸收超过60%。在LS180细胞中，随着抑制剂浓度（从5到50mM）的增加，利巴韦林和肌苷降低了400μM咪唑立宾的摄取。在没有细胞外钠的情况下，咪唑立宾的细胞摄取降至细胞外钠存在时摄取的72.7%，而100μM NBMPR将咪唑立宾的摄取显著降低至无NBMPR时的34.7%。这些发现表明，非钠依赖性核苷转运蛋白在很大程度上负责肠道中咪唑立宾的吸收。
