Kerb Reinhold
Department of Medical Science, AstraZeneca, R&D, Pepparedsleden 1, SE-43183 Mölndal, Sweden.
Cancer Lett. 2006 Mar 8;234(1):4-33. doi: 10.1016/j.canlet.2005.06.051. Epub 2006 Feb 28.
Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 (ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood-brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21A), and MRPs (ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.
药物转运体日益被视为药物处置和反应的关键决定因素。目前人们普遍认识到，ATP依赖的外排转运体MDR1（ABCB1，P-糖蛋白）在胃肠道、肝脏和肾脏等器官中的表达会显著改变药物吸收和排泄的程度。此外，血脑屏障水平上MDR1的表达限制了许多药物进入中枢神经系统。鉴于MDR1在药物处置过程中发挥如此重要的作用，越来越关注该转运体中的单核苷酸多态性（SNP）作为药物处置和药理反应个体间差异的潜在决定因素也就不足为奇了。然而，药物转运通常是上皮细胞基底外侧膜和顶端膜中外排泵和摄取泵协同作用的结果。在过去几年里，几乎在所有组织中都已识别并表征了越来越多参与多种药物内向或外向转运的跨膜蛋白，包括有机阴离子和阳离子转运体（OAT、OCT、溶质载体家族SLC22A）、有机阴离子转运蛋白（OATP、溶质载体家族SLCO，原SLC21A）以及MRP（ABCC），即ATP结合盒家族的其他成员。我们才刚刚开始认识到它们在药物递送和处置中的作用，以及这些转运蛋白中的基因多态性对药物治疗疗效和安全性个体间差异的影响。本综述总结了药物转运方面遗传差异对药物治疗的影响。主要聚焦于ABCB1，介绍了最新进展，并使用临床相关实例来说明遗传性药物转运差异如何有助于解释药物反应的个体差异。还简要介绍了其他转运体的药物遗传学。
