Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics

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• 作者：David J. Wagner ^{davidwag@uw.edu" class="auth_mail" title="E-mail the corresponding author} ; Tao Hu ^{taohu85@uw.edu" class="auth_mail" title="E-mail the corresponding author} ; Joanne Wang ; ^{jowang@uw.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Intracellular drug concentration ; Pharmacodynamics ; OCT ; MATE ; PMAT ; Drug transporter
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：111
• 期：Complete
• 页码：237-246
• 全文大小：1010 K

文摘

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 rational-based optimization of drug efficacy and safety.