Ieiri Ichiro, Takane Hiroshi, Hirota Takeshi, Otsubo Kenji, Higuchi Shun
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka, 812-8582, Japan.
Expert Opin Drug Metab Toxicol. 2006 Oct;2(5):651-74. doi: 10.1517/17425255.2.5.651.
There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.
药物转运体在药物治疗的药代动力学和药效学结果中的作用已得到越来越多的重视。药物转运体的临床相关性取决于其在人体组织中的定位（即矢量运动）、底物的治疗指数以及个体间固有的变异性。关于变异性，最近有报道称药物转运体基因的多态性与临床常用药物的药代动力学和药效学改变有关。越来越多的临床前和临床研究表明，遗传信息的应用可能有助于多种疾病的个体化药物治疗。然而，某些药物转运体基因变异的报道效应并不一致，在某些情况下，研究之间还存在冲突。此外，转运体基因中几乎所有已知变异的发生率往往具有种族依赖性。这些观察结果表明，在将一个种族群体获得的药代动力学数据外推至另一个种族群体之前，尤其是在药物开发的早期阶段，有必要考虑种族间的变异性。本综述从药代动力学和药效学角度重点关注药物转运体（ABC、有机阴离子和阳离子转运体）功能的遗传变异影响以及这些变异对药物治疗的意义。
