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Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions

The Pharmacogenomics Journal volume 15, pages 473–487 (2015)Cite this article

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Abstract

The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration–time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.

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References

  1. Volk C, Gorboulev V, Kotzsch A, Muller TD, Koepsell H . 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 2009; 76: 275–289.

    Article  CAS  PubMed  Google Scholar 

  2. Nies AT, Koepsell H, Damme K, Schwab M . Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol 2011; 201: 105–167.

    Article  CAS  Google Scholar 

  3. Koepsell H . The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 2013; 34: 413–435.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Schweifer N, Barlow DP . The Lx1 gene maps to mouse chromosome 17 and codes for a protein that is homologous to glucose and polyspecific transmembrane transporters. Mamm Genome 1996; 7: 735–740.

    Article  CAS  PubMed  Google Scholar 

  6. Terashita S, Dresser MJ, Zhang L, Gray AT, Yost SC, Giacomini KM . Molecular cloning and functional expression of a rabbit renal organic cation transporter. Biochim Biophys Acta 1998; 1369: 1–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Han TK, Everett RS, Proctor WR, Ng CM, Costales CL, Brouwer KL et al. Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol 2013; 84: 182–189.

    Article  CAS  PubMed  Google Scholar 

  14. Gilchrist SE, Alcorn J . Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam Clin Pharmacol 2010; 24: 205–214.

    CAS  PubMed  Google Scholar 

  15. Minuesa G, Purcet S, Erkizia I, Molina-Arcas M, Bofill M, Izquierdo-Useros N et al. Expression and functionality of anti-human immunodeficiency virus and anticancer drug uptake transporters in immune cells. J Pharmacol Exp Ther 2008; 324: 558–567.

    Article  CAS  PubMed  Google Scholar 

  16. Moreno-Navarrete JM, Ortega FJ, Rodriguez-Hermosa JI, Sabater M, Pardo G, Ricart W et al. OCT1 Expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes 2011; 60: 168–176.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Zhang H, Massey D, Tremelling M, Parkes M . Genetics of inflammatory bowel disease: clues to pathogenesis. Br Med Bull 2008; 87: 17–30.

    Article  CAS  PubMed  Google Scholar 

  19. Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY et al. Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents. J Neurochem 2010; 114: 717–727.

    Article  CAS  PubMed  Google Scholar 

  20. Jonker JW, Schinkel AH . Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther 2004; 308: 2–9.

    Article  CAS  PubMed  Google Scholar 

  21. Gupta S, Wulf G, Henjakovic M, Koepsell H, Burckhardt G, Hagos Y . Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther 2011; 341: 16–23.

    Article  PubMed  CAS  Google Scholar 

  22. More SS, Li S, Yee SW, Chen L, Xu Z, Jablons DM et al. Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Mol Cancer Ther 2010; 9: 1058–1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schaeffeler E, Hellerbrand C, Nies AT, Winter S, Kruck S, Hofmann U et al. DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. Genome Med 2011; 3: 82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Martinez-Becerra P, Vaquero J, Romero MR, Lozano E, Anadon C, Macias RI et al. No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm 2012; 9: 1693–1704.

    Article  CAS  PubMed  Google Scholar 

  25. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X et al. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9: 215–236.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Winter TN, Elmquist WF, Fairbanks CA . OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm 2011; 8: 133–142.

    Article  CAS  PubMed  Google Scholar 

  28. Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA et al. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci USA 2014; 111: 9983–9988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lovejoy KS, Todd RC, Zhang S, McCormick MS, D'Aquino JA, Reardon JT et al. cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects. Proc Natl Acad Sci USA 2008; 105: 8902–8907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Arimany-Nardi C, Montraveta A, Lee-Verges E, Puente XS, Koepsell H, Campo E et al. Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells. Pharmacogenomics J 2015; 15: 363–371.

    Article  CAS  PubMed  Google Scholar 

  32. Nies AT, Schwab M . Organic cation transporter pharmacogenomics and drug-drug interaction. Expert Rev Clin Pharmacol 2010; 3: 707–711.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 2008; 83: 273–280.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Christensen MM, Pedersen RS, Stage TB, Brasch-Andersen C, Nielsen F, Damkier P et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet Genomics 2013; 23: 526–534.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Umamaheswaran G, Praveen RG, Damodaran SE, Das AK, Adithan C . Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients. Clin Exp Med 2015; 15: 511–517.

    Article  CAS  PubMed  Google Scholar 

  39. Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, Hanson RL et al. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes 2010; 59: 2672–2681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tkac I, Klimcakova L, Javorsky M, Fabianova M, Schroner Z, Hermanova H et al. Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes. Diabetes Obes Metab 2013; 15: 189–191.

    Article  CAS  PubMed  Google Scholar 

  41. Christensen MM, Brasch-Andersen C, Green H, Nielsen F, Damkier P, Beck-Nielsen H et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics 2011; 21: 837–850.

    Article  CAS  PubMed  Google Scholar 

  42. Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ et al. A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 2011; 90: 674–684.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics 2012; 22: 659–666.

    Article  CAS  PubMed  Google Scholar 

  45. Gambineri A, Tomassoni F, Gasparini DI, Di Rocco A, Mantovani V, Pagotto U et al. Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 2010; 95: E204–E208.

    Article  CAS  PubMed  Google Scholar 

  46. Chen L, Takizawa M, Chen E, Schlessinger A, Segenthelar J, Choi JH et al. Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. J Pharmacol Exp Ther 2010; 335: 42–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yoon H, Cho HY, Yoo HD, Kim SM, Lee YB . Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. AAPS J 2013; 15: 571–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Jung N, Lehmann C, Rubbert A, Schomig E, Fatkenheuer G, Hartmann P et al. Organic cation transporters OCT1 and OCT2 determine the accumulation of lamivudine in CD4 cells of HIV-infected patients. Infection 2013; 41: 379–385.

    Article  CAS  PubMed  Google Scholar 

  50. Choi MK, Song IS . Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos 2012; 33: 170–178.

    Article  CAS  PubMed  Google Scholar 

  51. Herraez E, Lozano E, Macias RI, Vaquero J, Bujanda L, Banales JM et al. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology 2013; 58: 1065–1073.

    Article  CAS  PubMed  Google Scholar 

  52. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 2009; 15: 6062–6069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Arimany-Nardi C, Errasti-Murugarren E, Minuesa G, Martinez-Picado J, Gorboulev V, Koepsell H et al. Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors. Br J Pharmacol 2014; 171: 3868–3880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Minematsu T, Giacomini KM . Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 2011; 10: 531–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nies AT, Schaeffeler E, van der Kuip H, Cascorbi I, Bruhn O, Kneba M et al. Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clin Cancer Res 2014; 20: 985–994.

    Article  CAS  PubMed  Google Scholar 

  56. Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE . hOCT 1 and resistance to imatinib. Blood 2005; 106: 1133–1134.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC et al. 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 2006; 108: 697–704.

    Article  CAS  PubMed  Google Scholar 

  59. Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K et al. 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 2009; 15: 4750–4758.

    Article  CAS  PubMed  Google Scholar 

  60. Gromicho M, Magalhaes M, Torres F, Dinis J, Fernandes AR, Rendeiro P et al. Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib. Oncol Rep 2013; 29: 741–750.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  62. White DL, Saunders VA, Dang P, Engler J, Hughes TP . OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia 2010; 24: 1962–1965.

    Article  CAS  PubMed  Google Scholar 

  63. Maffioli M, Camos M, Gaya A, Hernandez-Boluda JC, Alvarez-Larran A, Domingo A et al. Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia. Leuk Res 2011; 35: 1014–1019.

    Article  CAS  PubMed  Google Scholar 

  64. Bazeos A, Marin D, Reid AG, Gerrard G, Milojkovic D, May PC et al. hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia 2010; 24: 1243–1245.

    Article  CAS  PubMed  Google Scholar 

  65. Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet 2010; 55: 731–737.

    Article  CAS  PubMed  Google Scholar 

  66. Singh O, Chan JY, Lin K, Heng CC, Chowbay B . SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One 2012; 7: e51771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Seong SJ, Lim M, Sohn SK, Moon JH, Oh SJ, Kim BS et al. Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol 2013; 24: 756–760.

    Article  CAS  PubMed  Google Scholar 

  68. Nambu T, Hamada A, Nakashima R, Yuki M, Kawaguchi T, Mitsuya H et al. Association of SLCO1B3 polymorphism with intracellular accumulation of imatinib in leukocytes in patients with chronic myeloid leukemia. Biol Pharm Bull 2011; 34: 114–119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T et al. Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit 2011; 33: 244–250.

    CAS  PubMed  Google Scholar 

  70. Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M et al. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica 2013; 98: 193–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Giannoudis A, Davies A, Lucas CM, Harris RJ, Pirmohamed M, Clark RE . Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood 2008; 112: 3348–3354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tzvetkov MV, Saadatmand AR, Lotsch J, Tegeder I, Stingl JC, Brockmoller J . Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther 2011; 90: 143–150.

    Article  CAS  PubMed  Google Scholar 

  73. Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmoller J . Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol 2013; 86: 666–678.

    Article  CAS  PubMed  Google Scholar 

  74. Fukuda T, Chidambaran V, Mizuno T, Venkatasubramanian R, Ngamprasertwong P, Olbrecht V et al. OCT1 genetic variants influence the pharmacokinetics of morphine in children. Pharmacogenomics 2013; 14: 1141–1151.

    Article  CAS  PubMed  Google Scholar 

  75. Saadatmand AR, Tadjerpisheh S, Brockmoller J, Tzvetkov MV . The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1. Biochem Pharmacol 2013; 83: 1427–1434.

    Article  CAS  Google Scholar 

  76. Tzvetkov MV, Saadatmand AR, Bokelmann K, Meineke I, Kaiser R, Brockmoller J . Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron. Pharmacogenomics J 2012; 12: 22–29.

    Article  CAS  PubMed  Google Scholar 

  77. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH . OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users. Neurogenetics 2011; 12: 79–82.

    Article  CAS  PubMed  Google Scholar 

  78. Dos Santos Pereira JN, Tadjerpisheh S, Abu Abed M, Saadatmand AR, Weksler B, Romero IA et al. The poorly membrane permeable antipsychotic drugs amisulpride and sulpiride are substrates of the organic cation transporters from the SLC22 family. AAPS J 2014; 16: 1247–1258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ahlin G, Chen L, Lazorova L, Chen Y, Ianculescu AG, Davis RL et al. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions. Pharmacogenomics J 2011; 11: 400–411.

    Article  CAS  PubMed  Google Scholar 

  80. Ohishi Y, Nakamuta M, Ishikawa N, Saitoh O, Nakamura H, Aiba Y et al. Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 2014; 49: 332–342.

    Article  CAS  PubMed  Google Scholar 

  81. O'Brien VP, Bokelmann K, Ramirez J, Jobst K, Ratain MJ, Brockmoller J et al. Hepatocyte nuclear factor 1 regulates the expression of the organic cation transporter 1 via binding to an evolutionary conserved region in intron 1 of the OCT1 gene. J Pharmacol Exp Ther 2013; 347: 181–192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rulcova A, Krausova L, Smutny T, Vrzal R, Dvorak Z, Jover R et al. Glucocorticoid receptor regulates organic cation transporter 1 (OCT1, SLC22A1) expression via HNF4alpha upregulation in primary human hepatocytes. Pharmacol Rep 2013; 65: 1322–1335.

    Article  CAS  PubMed  Google Scholar 

  83. Goswami S, Yee SW, Stocker S, Mosley JD, Kubo M, Castro R et al. Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 2014; 96: 370–379.

    Article  CAS  PubMed  Google Scholar 

  84. Grube M, Ameling S, Noutsias M, Kock K, Triebel I, Bonitz K et al. Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy. Am J Pathol 2011; 178: 2547–2559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bleasby K, Castle JC, Roberts CJ, Cheng C, Bailey WJ, Sina JF et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica 2006; 36: 963–988.

    Article  CAS  PubMed  Google Scholar 

  86. Salomon JJ, Muchitsch VE, Gausterer JC, Schwagerus E, Huwer H, Daum N et al. The cell line NCl-H441 is a useful in vitro model for transport studies of human distal lung epithelial barrier. Mol Pharm 2014; 11: 995–1006.

    Article  CAS  PubMed  Google Scholar 

  87. Zhang T, Xiang CD, Gale D, Carreiro S, Wu EY, Zhang EY . Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: implications for ocular drug disposition. Drug Metab Dispos 2008; 36: 1300–1307.

    Article  CAS  PubMed  Google Scholar 

  88. Bottalico B, Larsson I, Brodszki J, Hernandez-Andrade E, Casslen B, Marsal K et al. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta 2004; 25: 518–529.

    Article  CAS  PubMed  Google Scholar 

  89. Augustine LM, Markelewicz RJ Jr, Boekelheide K, Cherrington NJ . Xenobiotic and endobiotic transporter mRNA expression in the blood-testis barrier. Drug Metab Dispos 2005; 33: 182–189.

    Article  CAS  PubMed  Google Scholar 

  90. Bexten M, Oswald S, Grube M, Jia J, Graf T, Zimmermann U et al. Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics. Mol Pharm 2015; 12: 171–178.

    Article  CAS  PubMed  Google Scholar 

  91. Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler B et al. Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol 2012; 83: 805–814.

    Article  CAS  PubMed  Google Scholar 

  92. Hosotani R, Chowdhury P, McKay D, Rayford PL . Effect of L364718, a new CCK antagonist, on amylase secretion in isolated rat pancreatic acini. Pancreas 1988; 3: 95–98.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  96. Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S et al. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood 2013; 121: 628–637.

    Article  CAS  PubMed  Google Scholar 

  97. Grinfeld J, Gerrard G, Alikian M, Alonso-Dominguez J, Ale S, Valganon M et al. A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia. Br J Haematol 2013; 163: 631–639.

    Article  CAS  PubMed  Google Scholar 

  98. Di Paolo A, Polillo M, Capecchi M, Cervetti G, Barate C, Angelini S et al. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J 2014; 14: 328–335.

    Article  CAS  PubMed  Google Scholar 

  99. Jacobs C, Pearce B, Du Plessis M, Hoosain N, Benjeddou M . Genetic polymorphisms and haplotypes of the organic cation transporter 1 gene (SLC22A1) in the Xhosa population of South Africa. Genet Mol Biol 2014; 37: 350–359.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Du Plessis M, Pearce B, Jacobs C, Hoosain N, Benjeddou M . Genetic polymorphisms of the organic cation transporter 1 gene (SLC22A1) within the Cape Admixed population of South Africa. Mol Biol Rep 2014; 42: 665–672.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  102. Umamaheswaran G, Praveen RG, Arunkumar AS, Das AK, Shewade DG, Adithan C . Genetic analysis of OCT1 gene polymorphisms in an Indian population. Indian J Hum Genet 2011; 17: 164–168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all present and past members of the MPET laboratory. The UB laboratory is a member of the Oncology Program of the National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER ehd). CIBER ehd is an initiative of Instituto de Salud Carlos III (Spain). This study was partially supported by research funding from Ministerio de Ciencia e Innovación (SAF2011-23660 to MP-A and SAF2014-52067-R to MP-A), Generalitat de Catalunya (2009SGR624 to MP-A) and the Deutsche Forschungsgemeinschaft (KO 872/6-1 to HK).

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  1. Department of Biochemistry and Molecular Biology, Molecular Physiology and Experimental Therapeutics, Institute of Biomedicine (IBUB), University of Barcelona and Oncology Program, National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Barcelona, Spain

    C Arimany-Nardi & M Pastor-Anglada

  2. Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University Würzburg, Würzburg, Germany

    H Koepsell

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  1. C Arimany-Nardi
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  2. H Koepsell
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Correspondence to M Pastor-Anglada.

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Arimany-Nardi, C., Koepsell, H. & Pastor-Anglada, M. Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions. Pharmacogenomics J 15, 473–487 (2015). https://doi.org/10.1038/tpj.2015.78

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  • DOI: https://doi.org/10.1038/tpj.2015.78

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