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

Abstract

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.

Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters

“…The free plasma concentrations of methamphetamine in some abusers have been reported to be in the tens of micromolar range and even 130 M in one individual, indicating the potential to reach inhibitory concentrations of hOCT1-3 and hMATE1/2-K in vivo (de la Torre et al, 2004;Shima et al, 2008). Inhibition of hOCT1 and hOCT2 may reduce intracellular levels of some antiretrovirals in HIV-infected CD4 cells, reducing their effective concentration and efficacy at the site of action (Minuesa et al, 2008(Minuesa et al, , 2009Wagner et al, 2016). These potential distributional DDIs are This article has not been copyedited and formatted.…”

Altered Glycemic Control Associated With Polymorphisms in the SLC22A1 (OCT1) Gene in a Mexican Population With Type 2 Diabetes Mellitus Treated With Metformin: A Cohort Study

“…In addition, studies in the native population of the American continent have shown less control of blood glucose concentrations in comparison to European or Asian populations, who tend to have better metabolic control . Several studies have provided evidence that the effectiveness of metformin is affected by genetic variants in the transporters OCT1 ( SLC22A1 ), OCT2 ( SLC22A2 ), and MATE1 ( SLC47A1 ) . In particular, OCT1 plays an important role in the hepatic uptake of metformin, and the genetic variants in SLC22A1 have been widely studied and associated with the decreased efficacy of metformin.…”

“…Among these variants, rs622342, rs628031, and rs594709 have been shown to decrease the effectiveness of metformin in several populations . OCT2 and MATE1 are mainly expressed on the kidney and facilitate the excretion of metformin from tubular cells into urine . Studies in patients and in cell lines have demonstrated that the single‐nucleotide polymorphisms (SNPs) rs316019 and rs2289669 in the SLC22A and SLC47A1 genes, respectively, could exert an effect on the distribution and elimination of metformin .…”

Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids

“…In the human kidney, the basolateral hOCT2 and apical hMATEs sequentially mediate tubular secretion of many organic cation drugs (Wagner et al, 2016). According to the recent draft FDA guidance (Food and Drug Administration, 2012), OCT2 is one of three drug transporters in the human kidney recommended for evaluation for potential DDIs during drug development.…”