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Organic Cation Transporters (OCTs, MATEs), In Vitro and In Vivo Evidence for the Importance in Drug Therapy

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Book cover Drug Transporters

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 201))

Abstract

Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype–phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.

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References

  • Abel S, Nichols DJ, Brearley CJ, Eve MD (2000) Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Br J Clin Pharmacol 49:64–71

    CAS  PubMed  Google Scholar 

  • Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301:610–615

    CAS  PubMed  Google Scholar 

  • Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P et al (2008) Structural requirements for drug inhibition of the liver specific human organic cation transport protein. J Med Chem 51:5932–5942

    CAS  PubMed  Google Scholar 

  • Alnouti Y, Petrick JS, Klaassen CD (2006) Tissue distribution and ontogeny of organic cation transporters in mice. Drug Metab Dispos 34:477–482

    CAS  PubMed  Google Scholar 

  • Amphoux A, Vialou V, Drescher E, Bruss M, La Mannoury CC, Rochat C et al (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952

    CAS  PubMed  Google Scholar 

  • Aoyama N, Takahashi N, Kitaichi K, Ishihara R, Saito S, Maeno N et al (2006) Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. Alcohol Clin Exp Res 30:1644–1649

    CAS  PubMed  Google Scholar 

  • Asaka J, Terada T, Tsuda M, Katsura T, Inui K (2007) Identification of essential histidine and cysteine residues of the H+/organic cation antiporter multidrug and toxin extrusion (MATE). Mol Pharmacol 71:1487–1493

    CAS  PubMed  Google Scholar 

  • Ayrton A, Morgan P (2008) Role of transport proteins in drug discovery and development: a pharmaceutical perspective. Xenobiotica 38:676–708

    CAS  PubMed  Google Scholar 

  • Bachmakov I, Glaeser H, Fromm MF, König J (2008) Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on OATPs and OCT1. Diabetes 57:1463–1469

    CAS  PubMed  Google Scholar 

  • Bachmakov I, Glaeser H, Endress B, Morl F, König J, Fromm MF (2009) Interaction of beta-blockers with the renal uptake transporter OCT2. Diabetes Obes Metab 11:1080–1083

    CAS  PubMed  Google Scholar 

  • Baganz NL, Horton RE, Calderon AS, Owens WA, Munn JL, Watts LT et al (2008) Organic cation transporter 3: keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci U S A 105:18976–18981

    CAS  PubMed  Google Scholar 

  • Ballestero MR, Monte MJ, Briz O, Jimenez F, Gonzalez-San MF, Marin JJ (2006) Expression of transporters potentially involved in the targeting of cytostatic bile acid derivatives to colon cancer and polyps. Biochem Pharmacol 72:729–738

    CAS  PubMed  Google Scholar 

  • Barendt WM, Wright SH (2002) The human organic cation transporter (hOCT2) recognizes the degree of substrate ionization. J Biol Chem 277:22491–22496

    CAS  PubMed  Google Scholar 

  • Bayer M, Kuci Z, Schömig E, Gründemann D, Dittmann H, Handgretinger R et al (2009) Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells. Nucl Med Biol 36:287–294

    CAS  PubMed  Google Scholar 

  • Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH (2009a) Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 58:745–749

    CAS  PubMed  Google Scholar 

  • Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH (2009b) Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J 9:242–247

    CAS  PubMed  Google Scholar 

  • Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH (2010) Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics 20:38–44

    CAS  PubMed  Google Scholar 

  • Bednarczyk D, Ekins S, Wikel JH, Wright SH (2003) Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol 63:489–498

    CAS  PubMed  Google Scholar 

  • Biermann J, Lang D, Gorboulev V, Koepsell H, Sindic A, Schroter R et al (2006) Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol 290:C1521–C1531

    CAS  PubMed  Google Scholar 

  • Bourdet DL, Pritchard JB, Thakker DR (2005) Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther 315:1288–1297

    CAS  PubMed  Google Scholar 

  • Boyer JL, Graf J, Meier PJ (1992) Hepatic transport systems regulating pHi, cell volume, and bile secretion. Annu Rev Physiol 54:415–438

    CAS  PubMed  Google Scholar 

  • Budiman T, Bamberg E, Koepsell H, Nagel G (2000) Mechanism of electrogenic cation transport by the cloned organic cation transporter 2 from rat. J Biol Chem 275:29413–29420

    CAS  PubMed  Google Scholar 

  • Busch AE, Quester S, Ulzheimer JC, Waldegger S, Gorboulev V, Arndt P et al (1996) Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1. J Biol Chem 271:32599–32604

    CAS  PubMed  Google Scholar 

  • Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C et al (1998) Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol 54:342–352

    CAS  PubMed  Google Scholar 

  • Cetinkaya I, Ciarimboli G, Yalcinkaya G, Mehrens T, Velic A, Hirsch JR et al (2003) Regulation of human organic cation transporter hOCT2 by PKA, PI3K, and calmodulin-dependent kinases. Am J Physiol Renal Physiol 284:F293–F302

    CAS  PubMed  Google Scholar 

  • Chen Y, Zhang S, Sorani M, Giacomini KM (2007) Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. J Pharmacol Exp Ther 332:695–700

    Google Scholar 

  • Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK et al (2009a) Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics 19:497–504

    PubMed  Google Scholar 

  • Chen Y, Teranishi K, Li S, Yee SW, Hesselson S, Stryke D et al (2009b) Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function. Pharmacogenomics J 9:127–136

    CAS  PubMed  Google Scholar 

  • Cheng Y, Wright SH, Hooth MJ, Sipes IG (2009) Characterization of the disposition and toxicokinetics of N-butylpyridinium chloride in male F-344 rats and female B6C3F1 mice and its transport by organic cation transporter 2. Drug Metab Dispos 37:909–916

    CAS  PubMed  Google Scholar 

  • Ciarimboli G (2008) Organic cation transporters. Xenobiotica 38:936–971

    CAS  PubMed  Google Scholar 

  • Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E et al (2004) Regulation of the human organic cation transporter hOCT1. J Cell Physiol 201:420–428

    CAS  PubMed  Google Scholar 

  • Ciarimboli G, Ludwig T, Lang D, Pavenstädt H, Koepsell H, Piechota HJ et al (2005) Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 167:1477–1484

    CAS  PubMed  Google Scholar 

  • Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B et al (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is target for protective interventions. Am J Pathol 176(3):1169–1180

    CAS  PubMed  Google Scholar 

  • Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM (2002) Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res 19:1244–1247

    CAS  PubMed  Google Scholar 

  • Dudley AJ, Bleasby K, Brown CD (2000) The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK(1) cell monolayers. Br J Pharmacol 131:71–79

    CAS  PubMed  Google Scholar 

  • Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK et al (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40:316–321

    CAS  PubMed  Google Scholar 

  • Feng B, Obach RS, Burstein AH, Clark DJ, de Morais SM, Faessel HM (2008) Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro–in vivo study. Clin Pharmacol Ther 83:567–576

    CAS  PubMed  Google Scholar 

  • Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A (2009) Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther 86:396–402

    CAS  PubMed  Google Scholar 

  • Fujita T, Urban TJ, Leabman MK, Fujita K, Giacomini KM (2006) Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants. J Pharm Sci 95:25–36

    CAS  PubMed  Google Scholar 

  • Fukushima-Uesaka H, Maekawa K, Ozawa S, Komamura K, Ueno K, Shibakawa M et al (2004) Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab Pharmacokinet 19:239–244

    CAS  PubMed  Google Scholar 

  • Giacomini KM, Sugiyama Y (2006) Membrane transporters and drug response. In: Brunton LL, Lazo JS, Parker RL (eds) Goodman and Gilman’s. The pharmacological basis of therapeutics, 11th edn. McGraw Hill, New York, pp 41–70

    Google Scholar 

  • Giacomini KM, Hsyu PH, Gisclon LG (1988) Renal transport of drugs: an overview of methodology with application to cimetidine. Pharm Res 5:465–471

    CAS  PubMed  Google Scholar 

  • Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, Flockhart DA et al (2007) The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 81:328–345

    CAS  PubMed  Google Scholar 

  • Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S et al (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881

    CAS  PubMed  Google Scholar 

  • Gorboulev V, Volk C, Arndt P, Akhoundova A, Koepsell H (1999) Selectivity of the polyspecific cation transporter rOCT1 is changed by mutation of aspartate 475 to glutamate. Mol Pharmacol 56:1254–1261

    CAS  PubMed  Google Scholar 

  • Gorboulev V, Shatskaya N, Volk C, Koepsell H (2005) Subtype-specific affinity for corticosterone of rat organic cation transporters rOCT1 and rOCT2 depends on three amino acids within the substrate binding region. Mol Pharmacol 67:1612–1619

    CAS  PubMed  Google Scholar 

  • Gorbunov D, Gorboulev V, Shatskaya N, Mueller T, Bamberg E, Friedrich T et al (2008) High-affinity cation binding to organic cation transporter 1 induces movement of helix 11 and blocks transport after mutations in a modelled interaction domain between two helices. Mol Pharmacol 73:50–61

    CAS  PubMed  Google Scholar 

  • Gründemann D, Schömig E (2000) Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum Genet 106:627–635

    PubMed  Google Scholar 

  • Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552

    PubMed  Google Scholar 

  • Gründemann D, Schechinger B, Rappold GA, Schömig E (1998) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1:349–351

    PubMed  Google Scholar 

  • Gründemann D, Liebich G, Kiefer N, Köster S, Schömig E (1999) Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 56:1–10

    PubMed  Google Scholar 

  • Gründemann D, Hahne C, Berkels R, Schomig E (2003) Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J Pharmacol Exp Ther 304:810–817

    PubMed  Google Scholar 

  • Ha Choi J, Wah Yee S, Kim MJ, Nguyen L, Ho LJ, Kang JO et al (2009) Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1. Pharmacogenet Genomics 19:770–780

    PubMed  Google Scholar 

  • Hardman JG, Limbird LE, Gilman AG (eds) (2001) Goodman & Gilman's. The pharmacological basis of therapeutics, 10th edn. New York, McGraw Hill

    Google Scholar 

  • Harlfinger S, Fork C, Lazar A, Schömig E, Gründemann D (2005) Are organic cation transporters capable of transporting prostaglandins? Naunyn Schmiedebergs Arch Pharmacol 372:125–130

    CAS  PubMed  Google Scholar 

  • Hasannejad H, Takeda M, Narikawa S, Huang XL, Enomoto A, Taki K et al (2004) Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. Eur J Pharmacol 499:45–51

    CAS  PubMed  Google Scholar 

  • Hayer M, Bönisch H, Brüss M (1999) Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet 63:473–482

    CAS  PubMed  Google Scholar 

  • Hayer-Zillgen M, Brüss M, Bönisch H (2002) Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol 136:829–836

    CAS  PubMed  Google Scholar 

  • Hesselson SE, Matsson P, Shima JE, Fukushima H, Yee SW, Kobayashi Y et al (2009) Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation. PLoS One 4:e6942

    PubMed  Google Scholar 

  • Ho RH, Kim RB (2005) Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78:260–277

    CAS  PubMed  Google Scholar 

  • Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA et al (2008) Interaction of imatinib with human organic ion carriers. Clin Cancer Res 14:3141–3148

    CAS  PubMed  Google Scholar 

  • Inazu M, Takeda H, Matsumiya T (2003) Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem 84:43–52

    CAS  PubMed  Google Scholar 

  • International HapMap Consortium, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    CAS  PubMed  Google Scholar 

  • Ionita-Laza I, Lange C, Laird M (2009) Estimating the number of unseen variants in the human genome. Proc Natl Acad Sci U S A 106:5008–5013

    CAS  PubMed  Google Scholar 

  • Ito S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K et al (2010) Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther 333:341–350

    Google Scholar 

  • Itoda M, Saito Y, Maekawa K, Hichiya H, Komamura K, Kamakura S et al (2004) Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1). Drug Metab Pharmacokinet 19:308–312

    PubMed  Google Scholar 

  • Iwai M, Minematsu T, Narikawa S, Usui T, Kamimura H (2009) Involvement of human organic cation transporter 1 in the hepatic uptake of 1-(2-methoxyethyl)-2-methyl-4, 9-dioxo-3-(pyrazin-2-ylmethyl)-4, 9-dihydro-1H-napht ho[2, 3-d]imidazolium bromide (YM155 monobromide), a novel, small molecule survivin suppressant. Drug Metab Dispos 37:1856–1863

    CAS  PubMed  Google Scholar 

  • Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW et al (2001) Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol 21:5471–5477

    CAS  PubMed  Google Scholar 

  • Jonker JW, Wagenaar E, Van ES, Schinkel AH (2003) Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol 23:7902–7908

    CAS  PubMed  Google Scholar 

  • Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J et al (2008) Relevance of the organic cation transporters 1 and 2 for antiretroviral therapy in HIV infection. Drug Metab Dispos 36:1616–1623

    CAS  PubMed  Google Scholar 

  • Kaiser J (2008) DNA sequencing. A plan to capture human diversity in 1000 genomes. Science 319:395

    CAS  PubMed  Google Scholar 

  • Kajiwara M, Terada T, Ogasawara K, Iwano J, Katsura T, Fukatsu A et al (2009) Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. J Hum Genet 54:40–46

    CAS  PubMed  Google Scholar 

  • Kang HJ, Song IS, Shin HJ, Kim WY, Lee CH, Shim JC et al (2007) Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population. Drug Metab Dispos 35:667–675

    CAS  PubMed  Google Scholar 

  • Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH et al (1998) Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 273:15971–15979

    CAS  PubMed  Google Scholar 

  • Kerb R (2006) Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 234:4–33

    CAS  PubMed  Google Scholar 

  • Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E et al (2002) Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12:591–595

    CAS  PubMed  Google Scholar 

  • Khamdang S, Takeda M, Noshiro R, Narikawa S, Enomoto A, Anzai N et al (2002) Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 303:534–539

    CAS  PubMed  Google Scholar 

  • Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K et al (2009) Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res 15:4750–4758

    CAS  PubMed  Google Scholar 

  • Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H (2002) Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther 301:293–298

    CAS  PubMed  Google Scholar 

  • Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T et al (2005a) Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 20:379–386

    CAS  PubMed  Google Scholar 

  • Kimura N, Okuda M, Inui K (2005b) Metformin transport by renal basolateral organic cation transporter hOCT2. Pharm Res 22:255–259

    CAS  PubMed  Google Scholar 

  • Kimura N, Masuda S, Katsura T, Inui K (2009) Transport of guanidine compounds by human organic cation transporters, hOCT1 and hOCT2. Biochem Pharmacol 77:1429–1436

    CAS  PubMed  Google Scholar 

  • Kindla J, Fromm MF, König J (2009) In vitro evidence for the role of OATP and OCT uptake transporters in drug–drug interactions. Expert Opin Drug Metab Toxicol 5:489–500

    CAS  PubMed  Google Scholar 

  • Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck WH, Eichelbaum M et al (2005) Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 15:861–873

    CAS  PubMed  Google Scholar 

  • Kobara A, Hiasa M, Matsumoto T, Otsuka M, Omote H, Moriyama Y (2008) A novel variant of mouse MATE-1 H+/organic cation antiporter with a long hydrophobic tail. Arch Biochem Biophys 469:195–199

    CAS  PubMed  Google Scholar 

  • Koehler MR, Wissinger B, Gorboulev V, Koepsell H, Schmid M (1997) The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet Cell Genet 79:198–200

    CAS  PubMed  Google Scholar 

  • Koepsell H (1998) Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol 60:243–266

    CAS  PubMed  Google Scholar 

  • Koepsell H, Endou H (2004) The SLC22 drug transporter family. Pflugers Arch 447:666–676

    CAS  PubMed  Google Scholar 

  • Koepsell H, Schmitt BM, Gorboulev V (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150:36–90

    CAS  PubMed  Google Scholar 

  • Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251

    CAS  PubMed  Google Scholar 

  • Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081

    CAS  PubMed  Google Scholar 

  • Lai MY, Jiang FM, Chung CH, Chen HC, Chao PD (1988) Dose dependent effect of cimetidine on procainamide disposition in man. Int J Clin Pharmacol Ther Toxicol 26:118–121

    CAS  PubMed  Google Scholar 

  • Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H et al (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948

    CAS  PubMed  Google Scholar 

  • Lazar A, Gründemann D, Berkels R, Taubert D, Zimmermann T, Schömig E (2003) Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet 48:226–230

    CAS  PubMed  Google Scholar 

  • Lazar A, Zimmermann T, Koch W, Gründemann D, Schömig A, Kastrati A et al (2006) Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clin Exp Hypertens 28:645–653

    CAS  PubMed  Google Scholar 

  • Lazar A, Walitza S, Jetter A, Gerlach M, Warnke A, Herpertz-Dahlmann B et al (2008) Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol 11:35–48

    CAS  PubMed  Google Scholar 

  • Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE et al (2002) Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12:395–405

    CAS  PubMed  Google Scholar 

  • Lee WK, Reichold M, Edemir B, Ciarimboli G, Warth R, Koepsell H et al (2009) Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol 296:F1504–F1513

    CAS  PubMed  Google Scholar 

  • Li Q, Sai Y, Kato Y, Muraoka H, Tamai I, Tsuji A (2004) Transporter-mediated renal handling of nafamostat mesilate. J Pharm Sci 93:262–272

    CAS  PubMed  Google Scholar 

  • Lips KS, Volk C, Schmitt BM, Pfeil U, Arndt P, Miska D et al (2005) Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol 33:79–88

    CAS  PubMed  Google Scholar 

  • Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T et al (2006) Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol 17:2127–2135

    CAS  PubMed  Google Scholar 

  • Matsumoto T, Kanamoto T, Otsuka M, Omote H, Moriyama Y (2008) Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter. Am J Physiol Cell Physiol 294:C1074–C1078

    CAS  PubMed  Google Scholar 

  • Matsushima S, Maeda K, Inoue K, Ohta KY, Yuasa H, Kondo T et al (2009) The inhibition of human multidrug and toxin extrusion 1 is involved in the drug–drug interaction caused by cimetidine. Drug Metab Dispos 37:555–559

    CAS  PubMed  Google Scholar 

  • Meyer-Wentrup F, Karbach U, Gorboulev V, Arndt P, Koepsell H (1998) Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem Biophys Res Commun 248:673–678

    CAS  PubMed  Google Scholar 

  • Minematsu T, Iwai M, Umehara KI, Usui T, Kamimura H (2010) Characterization of human organic cation transporter 1 (OCT1/SLC22A1)-, and OCT2 (SLC22A2)-mediated transport of YM155 monobromide, a novel survivin suppressant. Drug Metab Dispos 38:1–4

    CAS  PubMed  Google Scholar 

  • Ming X, Ju W, Wu H, Tidwell RR, Hall JE, Thakker DR (2009) Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos 37:424–430

    CAS  PubMed  Google Scholar 

  • Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P et al (2009) Transport of lamivudine (3TC) and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther 329:252–261

    CAS  PubMed  Google Scholar 

  • Moore KH, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK et al (1996) Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther 59:550–558

    CAS  PubMed  Google Scholar 

  • Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M et al (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13:866–874

    CAS  PubMed  Google Scholar 

  • Müller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M (2005) Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70:1851–1860

    PubMed  Google Scholar 

  • Nagel G, Volk C, Friedrich T, Ulzheimer JC, Bamberg E, Koepsell H (1997) A reevaluation of substrate specificity of the rat cation transporter rOCT1. J Biol Chem 272:31953–31956

    CAS  PubMed  Google Scholar 

  • Neuhoff S, Ungell AL, Zamora I, Artursson P (2003) pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: implications for drug–drug interactions. Pharm Res 20:1141–1148

    CAS  PubMed  Google Scholar 

  • Nies AT, Herrmann E, Brom M, Keppler D (2008) Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1). Naunyn Schmiedebergs Arch Pharmacol 376:449–461

    CAS  PubMed  Google Scholar 

  • Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R et al (2009) Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50:1227–1240

    CAS  PubMed  Google Scholar 

  • Nishimura M, Naito S (2005) Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet 20:452–477

    CAS  PubMed  Google Scholar 

  • Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T et al (2008) Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet 53:607–614

    CAS  PubMed  Google Scholar 

  • Ohta KY, Inoue K, Hayashi Y, Yuasa H (2006) Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos 34:1868–1874

    CAS  PubMed  Google Scholar 

  • Okabe M, Szakacs G, Reimers MA, Suzuki T, Hall MD, Abe T et al (2008) Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters. Mol Cancer Ther 7:3081–3091

    CAS  PubMed  Google Scholar 

  • Okuda M, Kimura N, Inui K (2006) Interactions of fluoroquinolone antibacterials, DX-619 and levofloxacin, with creatinine transport by renal organic cation transporter hOCT2. Drug Metab Pharmacokinet 21:432–436

    CAS  PubMed  Google Scholar 

  • Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y (2005) A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A 102:17923–17928

    CAS  PubMed  Google Scholar 

  • Popp C, Gorboulev V, Muller TD, Gorbunov D, Shatskaya N, Koepsell H (2005) Amino acids critical for substrate affinity of rat organic cation transporter 1 line the substrate binding region in a model derived from the tertiary structure of lactose permease. Mol Pharmacol 67:1600–1611

    CAS  PubMed  Google Scholar 

  • Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900

    CAS  PubMed  Google Scholar 

  • Sakata T, Anzai N, Shin HJ, Noshiro R, Hirata T, Yokoyama H et al (2004) Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun 313:789–793

    CAS  PubMed  Google Scholar 

  • Sata R, Ohtani H, Tsujimoto M, Murakami H, Koyabu N, Nakamura T et al (2005) Functional analysis of organic cation transporter 3 expressed in human placenta. J Pharmacol Exp Ther 315:888–895

    CAS  PubMed  Google Scholar 

  • Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger UM et al (2001) Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 358:383–384

    CAS  PubMed  Google Scholar 

  • Schmitt BM, Koepsell H (2005) Alkali cation binding and permeation in the rat organic cation transporter rOCT2. J Biol Chem 280:24481–24490

    CAS  PubMed  Google Scholar 

  • Schmitt A, Mossner R, Gossmann A, Fischer IG, Gorboulev V, Murphy DL et al (2003) Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J Neurosci Res 71:701–709

    CAS  PubMed  Google Scholar 

  • Schmitt BM, Gorbunov D, Schlachtbauer P, Egenberger B, Gorboulev V, Wischmeyer E et al (2009) Charge-to-substrate ratio during organic cation uptake by rat OCT2 is voltage dependent and altered by exchange of glutamate 448 with glutamine. Am J Physiol Renal Physiol 296:F709–F722

    CAS  PubMed  Google Scholar 

  • Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K et al (2007) Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet 52:117–122

    CAS  PubMed  Google Scholar 

  • Shnitsar V, Eckardt R, Gupta S, Grottker J, Muller GA, Koepsell H et al (2009) Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine. Cancer Res 69:1494–1501

    CAS  PubMed  Google Scholar 

  • Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D et al (2003) Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A 100:5902–5907

    CAS  PubMed  Google Scholar 

  • Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431

    CAS  PubMed  Google Scholar 

  • Shu Y, Brown C, Castro R, Shi R, Lin E, Owen R et al (2008) Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280

    CAS  PubMed  Google Scholar 

  • Siva N (2008) 1000 Genomes project. Nat Biotechnol 26:256

    PubMed  Google Scholar 

  • Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23:545–551

    CAS  PubMed  Google Scholar 

  • Song I, Shin H, Shim E, Jung I, Kim W, Shon J et al (2008) Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther 84:559–562

    CAS  PubMed  Google Scholar 

  • Sturm A, Gorboulev V, Gorbunov D, Keller T, Volk C, Schmitt BM et al (2007) Identification of cysteines in rat organic cation transporters rOCT1 (C322, C451) and rOCT2 (C451) critical for transport activity and substrate affinity. Am J Physiol Renal Physiol 293:F767–F779

    CAS  PubMed  Google Scholar 

  • Suhre WM, Ekins S, Chang C, Swaan PW, Wright SH (2005) Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2. Mol Pharmacol 67:1067–1077

    CAS  PubMed  Google Scholar 

  • Tachampa K, Takeda M, Khamdang S, Noshiro-Kofuji R, Tsuda M, Jariyawat S et al (2008) Interactions of organic anion transporters and organic cation transporters with mycotoxins. J Pharmacol Sci 106:435–443

    CAS  PubMed  Google Scholar 

  • Tahara H, Kusuhara H, Endou H, Koepsell H, Imaoka T, Fuse E et al (2005) A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther 315:337–345

    CAS  PubMed  Google Scholar 

  • Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T et al (2002) Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther 300:918–924

    CAS  PubMed  Google Scholar 

  • Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K (2007) Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol 74:359–371

    CAS  PubMed  Google Scholar 

  • Tanihara Y, Masuda S, Katsura T, Inui KI (2009) Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2. Biochem Pharmacol 78:1263–1271

    CAS  PubMed  Google Scholar 

  • Taubert D, Grimberg G, Stenzel W, Schömig E (2007) Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons. PLoS One 2:e385

    PubMed  Google Scholar 

  • Terada T, Inui KI (2008) Physiological and pharmacokinetic roles of H(+)/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol 75:1689–1696

    CAS  PubMed  Google Scholar 

  • Terada T, Masuda S, Asaka J, Tsuda M, Katsura T, Inui K (2006) Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res 23:1696–1701

    CAS  PubMed  Google Scholar 

  • Thomas J, Wang L, Clark RE, Pirmohamed M (2004) Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104:3739–3745

    CAS  PubMed  Google Scholar 

  • Tregouet DA, Konig IR, Erdmann J, Munteanu A, Braund PS, Hall AS et al (2009) Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 41:283–285

    CAS  PubMed  Google Scholar 

  • Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui KI (2009a) Targeted disruption of the multidrug and toxin extrusion 1 (Mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol 75:1280–1286

    CAS  PubMed  Google Scholar 

  • Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T et al (2009b) Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther 329:185–191

    CAS  PubMed  Google Scholar 

  • Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D et al (2009) The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 86:299–306

    CAS  PubMed  Google Scholar 

  • Umehara KI, Iwatsubo T, Noguchi K, Usui T, Kamimura H (2008) Effect of cationic drugs on the transporting activity of human and rat OCT/Oct 1–3 in vitro and implications for drug–drug interactions. Xenobiotica 38:1203–1218

    CAS  PubMed  Google Scholar 

  • Urakami Y, Kimura N, Okuda M, Inui K (2004) Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm Res 21:976–981

    CAS  PubMed  Google Scholar 

  • van Crugten J, Bochner F, Keal J, Somogyi A (1986) Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs. J Pharmacol Exp Ther 236:481–487

    PubMed  Google Scholar 

  • van Montfoort JE, Muller M, Groothuis GM, Meijer DK, Koepsell H, Meier PJ (2001) Comparison of “type I” and “type II” organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther 298:110–115

    PubMed  Google Scholar 

  • Verhaagh S, Schweifer N, Barlow DP, Zwart R (1999) Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26–q27. Genomics 55:209–218

    CAS  PubMed  Google Scholar 

  • Vialou V, Amphoux A, Zwart R, Giros B, Gautron S (2004) Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci 24:2846–2851

    Google Scholar 

  • Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106:1471–1482

    CAS  PubMed  Google Scholar 

  • Volk C, Gorboulev V, Kotzsch A, Muller TD, Koepsell H (2009) Five amino acids in the innermost cavity of the substrate binding cleft of organic cation transporter 1 interact with extracellular and intracellular corticosterone. Mol Pharmacol 76:275–289

    CAS  PubMed  Google Scholar 

  • Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302:510–515

    CAS  PubMed  Google Scholar 

  • Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y (2003) Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 63:844–848

    CAS  PubMed  Google Scholar 

  • Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE (2008a) Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 83:258–264

    CAS  PubMed  Google Scholar 

  • Wang ZJ, Yin OQ, Tomlinson B, Chow MS (2008b) OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics 18:637–645

    CAS  PubMed  Google Scholar 

  • White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC et al (2006) OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 108:697–704

    CAS  PubMed  Google Scholar 

  • White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al (2007) Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 110:4064–4072

    CAS  PubMed  Google Scholar 

  • Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway S et al (2000) Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. Am J Physiol Renal Physiol 279:F449–F458

    CAS  PubMed  Google Scholar 

  • Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF et al (2009) Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm 116:689–697

    CAS  PubMed  Google Scholar 

  • Yokoo S, Masuda S, Yonezawa A, Terada T, Katsura T, Inui KI (2008) Significance of OCT3/SLC22A3, organic cation transporter 3, expression for the cytotoxic effect of oxaliplatin in colorectal cancer. Drug Metab Dispos 36:2299–2306

    CAS  PubMed  Google Scholar 

  • Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui KI (2006) Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and MATE family). J Pharmacol Exp Ther 319:879–886

    CAS  PubMed  Google Scholar 

  • Zach O, Krieger O, Foedermayr M, Zellhofer B, Lutz D (2008) OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in chronic myeloid leukemia patients. Leuk Lymphoma 49:2222–2223

    CAS  PubMed  Google Scholar 

  • Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giacomini KM (1997) Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 51:913–921

    CAS  PubMed  Google Scholar 

  • Zhang L, Schaner ME, Giacomini KM (1998) Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286:354–361

    CAS  PubMed  Google Scholar 

  • Zhang L, Gorset W, Washington CB, Blaschke TF, Kroetz DL, Giacomini KM (2000) Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system. Drug Metab Dispos 28:329–334

    CAS  PubMed  Google Scholar 

  • Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A et al (2006) Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 66:8847–8857

    CAS  PubMed  Google Scholar 

  • Zhang X, Cherrington NJ, Wright SH (2007) Molecular identification and functional characterization of rabbit MATE1 and MATE2-K. Am J Physiol Renal Physiol 293:F360–F370

    CAS  PubMed  Google Scholar 

  • Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G et al (2009) Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes 58:1434–1439

    CAS  PubMed  Google Scholar 

  • Zolk O, Solbach TF, König J, Fromm MF (2008) Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2). Naunyn Schmiedebergs Arch Pharmacol 379:337–348

    PubMed  Google Scholar 

  • Zolk O, Solbach TF, König J, Fromm MF (2009) Functional characterization of the human organic cation transporter 2 variant p. 270Ala>Ser. Drug Metab Dispos 37:1312–1318

    CAS  PubMed  Google Scholar 

  • Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, Barlow DP (2001) Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 21:4188–4196

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors’ work on the importance of transporters in drug therapy is supported by the Robert-Bosch Foundation Stuttgart, the IZEPHA Grants #6-0-0/672 and #8-0-0/674, the Federal Ministry for Education and Research (BMBF, Berlin, Germany) grant 03 IS 2061C, the German Research Foundation Grant SFB487/A4, and the Deutsche Krebshilfe (grant 107150). We thank Dr. Elke Schaeffeler for helpful discussions.

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Authors and Affiliations

  1. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Anne T. Nies, Katja Damme & Matthias Schwab

  2. University of Tübingen, Tübingen, Germany

    Anne T. Nies & Katja Damme

  3. Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany

    Hermann Koepsell

  4. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany

    Matthias Schwab

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  1. Anne T. Nies
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  2. Hermann Koepsell
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Correspondence to Anne T. Nies .

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  1. Inst. Experimentelle und Klinische, Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Fahrstr. 17, Erlangen, 91054, Germany

    Martin F. Fromm

  2. Division of Clinical Pharmacology, University of Western Ontario, Windmere Road 339, London, N6A 5A5, Ontario, Canada

    Richard B. Kim

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Nies, A.T., Koepsell, H., Damme, K., Schwab, M. (2011). Organic Cation Transporters (OCTs, MATEs), In Vitro and In Vivo Evidence for the Importance in Drug Therapy. In: Fromm, M., Kim, R. (eds) Drug Transporters. Handbook of Experimental Pharmacology, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14541-4_3

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