Shitara Yoshihisa, Horie Toshiharu, Sugiyama Yuichi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chou-ku, Chiba 260-8675, Japan.
Eur J Pharm Sci. 2006 Apr;27(5):425-46. doi: 10.1016/j.ejps.2005.12.003. Epub 2006 Feb 20.
Transporters play an important role in the processes of drug absorption, distribution and excretion. In this review, we have focused on the involvement of transporters in drug excretion in the liver and kidney. The rate of transporter-mediated uptake and efflux determines the rate of renal and hepatobiliary elimination. Transporters are thus important as a determinant of the clearance in the body. Even when drugs ultimately undergo metabolism, their elimination rate is sometimes determined by the uptake rate mediated by transporters. Transporters regulate the pharmacological and/or toxicological effect of drugs because they limit their distribution to tissues responsible for their effect and/or toxicity. For example, the liver-specific distribution of some statins via organic anion transporters helps them to produce their high pharmacological effect. On the other hand, as in the case of metformin taken up by organic cation transporter 1, drug distribution to the tissue(s) may enhance its toxicity. As transporter-mediated uptake is a determinant of the drug elimination rate, drug-drug interactions involving the process of transporter-mediated uptake can occur. In this review, we have introduced some examples and described their mechanisms. More recently, some methods to analyze such transporter-mediated transport have been reported. The estimation of the contributions of transporters to the net clearance of a drug makes it possible to predict the net clearance from data involving drug transport in transporter-expressing cells. Double transfected cells, where both uptake and efflux transporters are expressed on the same polarized cells, are also helpful for the analysis of the rate of transporter-mediated transcellular transport.
转运体在药物吸收、分布和排泄过程中发挥着重要作用。在本综述中，我们重点关注了转运体在肝脏和肾脏药物排泄中的作用。转运体介导的摄取和外排速率决定了肾脏和肝胆清除率。因此，转运体作为体内清除率的一个决定因素非常重要。即使药物最终会经历代谢，其消除速率有时也由转运体介导的摄取速率决定。转运体调节药物的药理和/或毒理作用，因为它们限制了药物向负责其作用和/或毒性的组织的分布。例如，一些他汀类药物通过有机阴离子转运体在肝脏中的特异性分布有助于它们产生高效药理作用。另一方面，就像二甲双胍通过有机阳离子转运体1摄取的情况一样，药物向组织的分布可能会增强其毒性。由于转运体介导的摄取是药物消除速率的一个决定因素，因此可能会发生涉及转运体介导摄取过程的药物相互作用。在本综述中，我们介绍了一些例子并描述了它们的机制。最近，已经报道了一些分析这种转运体介导转运的方法。估计转运体对药物净清除率的贡献使得从涉及在表达转运体的细胞中进行药物转运的数据预测净清除率成为可能。双转染细胞，即在同一极化细胞上同时表达摄取和外排转运体的细胞，也有助于分析转运体介导的跨细胞转运速率。
