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ObjectiveThe goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin.MethodsThe uptake of metformin was performed in stably t

The human organic cation transporter 2 (OCT2, SLC22A2 ) is a multispecific transporter of organic cations, including many clinically used drugs. OCT2 is primarily responsible for the uptake of organic cations across the basolateral membrane of renal tubular epithelial cells and is considered a major transporter in the active secretion of organic cations in the kidney. Uptake of organic cations by OCT2 is driven by the inside-negative membrane potential and is pH-sensitive. Regulation of OCT2 at the transcriptional level by steroid hormones and at the protein level by various protein kinases has been described. Several human genetic variants in the coding region of OCT2 have been identified and functionally characterized, including both polymorphic and rare variants. A variety of structurally diverse compounds have been shown to interact with OCT2, including endogenous compounds, drugs, and dietary supplements. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

The completion of the Human Genome Project and the development of high-throughput polymorphism identification methods have allowed researchers to carry out full genetic analyses of many clinically relevant genes. However, few studies have combined genetic analysis with in vitro phenotyping to better understand the relationship between genetic variation and protein function. Many transporters in the kidney are thought to play key roles in defense against a variety of foreign substances. The goal of this study was to understand the relationship between variation in a gene encoding a major renal xenobiotic transporter, OCT2, and transporter function. We report a comprehensive genetic analysis and functional characterization of variants of OCT2. Twenty-eight variable sites in the OCT2 gene were identified in a collection of 247 ethnically diverse DNA samples. Eight caused non-synonymous amino acid changes, of which four were present at/= 1% in an ethnic population. All four of these altered transporter function assayed in Xenopus laevis oocytes. Analysis of nucleotide diversity (pi) revealed a higher prevalence of synonymous (pi = 22.4 x 10-4) versus non-synonymous (pi = 2.1 x 10-4) changes in OCT2 than in other genes. In addition, the non-synonymous sites had a significant tendency to exhibit more skewed allele frequencies (more negative Tajima's D-values) compared to synonymous sites. The population-genetic analysis, together with the functional characterization, suggests that selection has acted against amino acid changes in OCT2. This selection may be due to a necessary role of OCT2 in the renal elimination of endogenous amines or xenobiotics, including environmental toxins, neurotoxic amines and therapeutic drugs.

Transporters in the kidney mediate the secretion or reabsorption of many compounds and thereby influence the plasma levels of their substrates. Organic anion transporters and organic cation transporters are two major classes of secretory transporters in the mammalian kidney. During the past decade, significant progress has been made in the cloning, functional expression, and initial characterization of these transporters. To date, five organic cation transporters and nine organic anion transporters have been cloned. In this review, we summarize the available data on organic anion and organic cation transporters, focusing in particular on their molecular characteristics, tissue distribution, and inhibitor and substrate selectivities. Currently we have a good understanding of the inhibitor selectivities for most of these transporters, and with the development of more robust assays, we will soon have a better understanding of their substrate selectivities. Based on the available data, summarized in this review, it appears that many compounds interact with multiple transporters. Futhermore, there appears to be substantial overlap in the selectivities of organic cation transporters, and the same appears true for organic anion transporters. At the present time, it is unclear what the roles of these multiple transporters are in renal drug elimination. With the development of new assays, reagents, and experimental methods, we will soon have a better understanding of the roles of each transporter isoform in the renal elimination of drugs. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:397–421, 2001

Renal excretion is the major pathway for elimination of many clinically used drugs and xenobiotics. We estimated the genetic component (rGC) contributing to variation in renal clearance for six compounds (amoxicillin, ampicillin, metformin, terodiline, digoxin and iohexol) using Repeated Drug Application methodology. Data were obtained from published literature. The rGC values of renal clearance of metformin, amoxicillin, and ampicillin, which undergo transporter-mediated secretion, ranged from 0.64-0.94. This finding suggests that variation in the renal clearance of these drugs has a strong genetic component. Additionally, the rGC values of renal clearance of metformin, amoxicillin, and ampicillin were similar to previously reported rGC values for metabolism. By contrast, the rGC values of renal clearance for iohexol, digoxin, and terodiline were low (0.12-0.37). Renal clearance of these compounds occurs mainly through passive processes (e.g. glomerular filtration and passive secretion/reabsorption). The low rGC values of iohexol, digoxin and terodiline suggest that environmental factors may contribute to variation in their renal clearance.