Takaai Mari, Morishita Hiroki, Ishida Kazuya, Taguchi Masato, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Eur J Pharmacol. 2008 Dec 28;601(1-3):61-5. doi: 10.1016/j.ejphar.2008.10.047. Epub 2008 Nov 6.
The aim of the present study was to characterize the intestinal absorption of ribavirin (1-beta-d-ribofuranosyl-1, 2, 4-trizole-3-carboxamide). We evaluated the contribution of Na(+)-dependent and -independent transport to ribavirin absorption in the rat intestine using an in situ closed loop method. In addition, we performed pharmacokinetic analysis of the uptake of ribavirin in human intestinal epithelial LS180 cells, and also evaluated the effect of extracellular Na(+) concentration and an inhibitor of the Na(+)-independent equilibrative nucleoside transporter, nitrobenzylmercaptopurine ribonucleoside (NBMPR), on the uptake of ribavirin in the cells. In the presence and also absence of Na(+) in rat intestinal loops, more than 80% of the administered dose (50 microg at a concentration of 100 microg/ml=409 microM) of ribavirin was absorbed in 40 min. The absorption of ribavirin in the rat intestine was significantly reduced by coadministration of 10 mg/ml (=37.3 mM) inosine. In LS180 cells, 100 microM ribavirin was taken up time-dependently, and the influx clearance of the drug was similar to the efflux clearance. Five mM inosine and mizoribine reduced the uptake of 100 microM ribavirin in LS180 cells. The absence of extracellular Na(+) decreased the uptake of 100 microM ribavirin only weakly in the cells, whereas the uptake of 100 microM-2 mM ribavirin was markedly decreased by 100 microM NBMPR. These findings suggested that Na(+)-independent nucleoside transport contributes significantly to intestinal absorption of ribavirin at relatively high concentrations (>or=100 microM).
本研究的目的是表征利巴韦林（1-β-D-呋喃核糖基-1,2,4-三唑-3-甲酰胺）的肠道吸收情况。我们使用原位闭环法评估了钠依赖性和非依赖性转运对大鼠肠道中利巴韦林吸收的贡献。此外，我们对人肠上皮LS180细胞中利巴韦林的摄取进行了药代动力学分析，并评估了细胞外钠浓度和非钠依赖性平衡核苷转运体抑制剂硝基苄基巯基嘌呤核糖核苷（NBMPR）对细胞中利巴韦林摄取的影响。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 = 409μM时为50μg）的利巴韦林在40分钟内有超过80%被吸收。同时给予10mg/ml（= 37.3mM）肌苷可显著降低大鼠肠道中利巴韦林的吸收。在LS180细胞中，100μM利巴韦林的摄取呈时间依赖性，药物的流入清除率与流出清除率相似。5mM肌苷和米唑立宾降低了LS180细胞中100μM利巴韦林的摄取。细胞外钠的缺失仅轻微降低了细胞中100μM利巴韦林的摄取，而100μM NBMPR则显著降低了100μM - 2mM利巴韦林的摄取。这些发现表明，在相对高浓度（≥100μM）时，非钠依赖性核苷转运对利巴韦林的肠道吸收有显著贡献。
