Graduate School for Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
Biophys Chem. 2010 Mar;147(1-2):59-65. doi: 10.1016/j.bpc.2009.12.012. Epub 2010 Jan 6.
Transport across the cell membrane is crucial in drug delivery. However, the process is complicated because nucleoside derivatives that are commonly used as anti-viral drugs are transported through two different types of specific transporters: concentrative transporters and equilibrative transporters. Cross-disciplinary approaches involving both biological experiments and theoretical considerations are therefore necessary to study the transport of nucleoside analogues such as ribavirin. Here we constructed an experimental model system using the Xenopus laevis oocyte that expressed examples of both types of transporters: human concentrative nucleoside transporter 3 and human equilibrative transporter 1. We also performed a kinetic study. Experimental results showed that the transport of ribavirin could be reduced by inhibiting one of the two types of transporters, which seems to be counterintuitive. We therefore designed a simple mathematical model of the dynamics of ribavirin uptake and analyzed the model behaviors using a numerical simulation. The theoretical results reproduced the experimentally observed phenomena and suggested a possible mechanism for the process. Based on this mechanism, we predicted some potential methods for the effective uptake of ribavirin from a dynamics point of view.
跨细胞膜转运对于药物输送至关重要。然而，由于常用于抗病毒药物的核苷衍生物是通过两种不同类型的特定转运体：协同转运体和平衡转运体来转运的，因此需要涉及生物实验和理论考虑的跨学科方法来研究核苷类似物如利巴韦林的转运。在这里，我们使用表达两种转运体（人高亲和性核苷转运体 3 和人平衡转运体 1）的非洲爪蟾卵母细胞构建了一个实验模型系统。我们还进行了动力学研究。实验结果表明，通过抑制两种转运体之一，可降低利巴韦林的转运，这似乎有违直觉。因此，我们设计了一个利巴韦林摄取动力学的简单数学模型，并通过数值模拟分析了模型行为。理论结果再现了实验观察到的现象，并提出了该过程的可能机制。基于该机制，我们从动力学角度预测了一些有效摄取利巴韦林的潜在方法。
