Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics.
Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics.
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DOI：
10.1016/j.phrs.2016.06.002
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发表时间：
2016-09
影响因子：
9.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wagner DJ;Hu T;Wang J
大多数药物旨在作用于驻留在特定组织或细胞类型内的分子靶标。因此，靶组织或细胞内的药物浓度与其药理作用最相关。越来越多的证据表明，药物转运蛋白不仅在控制全身药物浓度方面发挥重要作用，而且还是组织内和细胞内药物浓度的重要守门人。本文综述了多特异性有机阳离子转运蛋白，包括有机阳离子转运蛋白1-3（OCT 1 -3）、多药和毒素排出蛋白1-2（MATE 1 -2）和质膜单胺转运蛋白（PMAT）。在概述了这些转运蛋白的组织分布、转运机制和功能特征后，我们重点介绍了证明局部表达的OCT能够影响细胞内药物浓度并直接影响其药理学和毒理学活性的研究。具体而言，OCT 1介导的二甲双胍进入其在肝脏中的作用位点受到OCT 1的遗传多态性和化学抑制的影响。综述了肾脏OCT 2和MATE 1/2-K对顺铂肾内蓄积和肾毒性的影响。新的数据表明，在唾液中的药物积累和分泌的OCT 3的作用进行了讨论。在可能的情况下，根据组织内和细胞内药物暴露，介绍并讨论药效学反应和毒理学效应。目前的挑战，知识差距和未来的研究方向进行了讨论。了解转运蛋白对组织内和细胞内药物浓度的影响对于基于合理性的药物疗效和安全性优化具有重要意义。
Most drugs are intended to act on molecular targets residing within a specific tissue or cell type. Therefore, the drug concentration within the target tissue or cells is most relevant to its pharmacological effect. Increasing evidences suggest that drug transporters not only play a significant role in governing systemic drug levels, but are also an important gate keeper for intra-tissue and intracellular drug concentrations. This review focuses on polyspecific organic cation transporters, which include the organic cation transporters 1-3 (OCT1-3), the multidrug and toxin extrusion proteins 1-2 (MATE1-2) and the plasma membrane monoamine transporter (PMAT). Following an overview of the tissue distribution, transport mechanisms, and functional characteristics of these transporters, we highlight the studies demonstrating the ability of locally expressed OCTs to impact intracellular drug concentrations and directly influence their pharmacological and toxicological activities. Specifically, OCT1-mediated metformin access to its site of action in the liver is impacted by genetic polymorphisms and chemical inhibition of OCT1. The impact of renal OCT2 and MATE1/2-K in cisplatin intrarenal accumulation and nephrotoxicity is reviewed. New data demonstrating the role of OCT3 in salivary drug accumulation and secretion is discussed. Whenever possible, the pharmacodynamic response and toxicological effects is presented and discussed in light of intra-tissue and intracellular drug exposure. Current challenges, knowledge gaps, and future research directions are discussed. Understanding the impact of transporters on intra-tissue and intracellular drug concentrations has important implications for rationale-based optimization of drug efficacy and safety.