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Genetic Variability in Organic Cation Transporters: Pathophysiological Manifestations and Consequences for Drug Pharmacokinetics and Efficacy

  • Mladen Vassilev TzvetkovEmail author
  • Nawar Dalila
  • Frank Faltraco
Chapter

Abstract

Naturally occurring genetic variants may affect expression and function of organic cation transporters. This may result in inter-individual variations of plasma and organ concentrations of endogenous molecules and drugs. Hence, genetic variants in the organic cation transporters may confer susceptibility to diseases and may cause variations in drug pharmacokinetics, efficacy and toxicity.

This chapter gives a structured overview of the genetic variability in the human organic cation transporters and its consequences for disease susceptibility and therapeutic drug response. We present in a special depth the available information about genetically-determined loss of OCT1 activity and the consequences for the pharmacokinetics, efficacy and toxicity of drugs like metformin, morphine, tramadol and tropisetron. Another special focus is on polymorphisms in OCTN1 and OCTN2 as risk factors for Crohn’s disease. The third focus is on the accumulating data about the effects of regulatory polymorphisms in the MATE1 and MATE2K genes on metformin pharmacokinetics and efficacy. We also present meta-analyses of the currently available studies about the effects of the OCT2 polymorphism Ala270Ser on metformin pharmacokinetics.

Keywords

Organic cation transporter Genetic polymorphisms SNPs Crohn’s disease Pharmacokinetics Drug efficacy Metformin Morphine Tramadol Tropisetron Cisplatin 

References

  1. 1.
    Consortium GP, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.CrossRefGoogle Scholar
  2. 2.
    Takeuchi A, Motohashi H, Okuda M, Inui K. Decreased function of genetic variants, Pro283Leu and Arg287Gly, in human organic cation transporter hOCT1. Drug Metab Pharmacokinet. 2003;18:409–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002;12:591–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, et al. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A. 2003;100:5902–7.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422–31.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Chen L, Takizawa M, Chen E, Schlessinger A, Segenthelar J, Choi JH, Sali A, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Ahlin G, Chen L, Lazorova L, Chen Y, Ianculescu AG, Davis RL, Giacomini KM, et al. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions. Pharmacogenomics J. 2011;11:400–11.PubMedCrossRefGoogle Scholar
  8. 8.
    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;86:666–78.PubMedCrossRefGoogle Scholar
  9. 9.
    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;12:22–9.PubMedCrossRefGoogle Scholar
  10. 10.
    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;90:143–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, Sabolic I, 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.PubMedCrossRefGoogle Scholar
  12. 12.
    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. 2012;83:1427–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Tzvetkov MV, Seitz T, Bokelmann K, Mueller T, Brockmoller J, Koepsell H. Does the haplotype Met408-Del420, which was apparently predictive for imatinib efficacy, really exist and how strongly may it affect OCT1 activity? Blood. 2014;123:1427–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, Fridmanis D, 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;22:659–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, et al. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A. 2014;111:9983–8.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Grinfeld J, Gerrard G, Alikian M, Alonso-Dominguez J, Ale S, Valganon M, Nteliopoulos G, 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;163:631–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, et al. Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011;477:54–60.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    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;9:242–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genomics. 2010;20:38–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Ohishi Y, Nakamuta M, Ishikawa N, Saitoh O, Nakamura H, Aiba Y, Komori A, et al. Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol. 2014;49:332–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Song IS, Shin HJ, Shin JG. Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes. Xenobiotica. 2008;38:1252–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics. 2002;12:395–405.PubMedCrossRefGoogle Scholar
  24. 24.
    Franke RM, Kosloske AM, Lancaster CS, Filipski KK, Hu C, Zolk O, Mathijssen RH, et al. Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-beta-D-glucosaminidase. Clin Cancer Res. 2010;16:4198–206.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Zolk O, Solbach TF, Konig J, Fromm MF. Functional characterization of the human organic cation transporter 2 variant p. 270Ala>Ser. Drug Metab Dispos. 2009;37:1312–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Song IS, Shin HJ, Shim EJ, Jung IS, Kim WY, Shon JH, Shin JG. Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther. 2008;84:559–62.PubMedCrossRefGoogle Scholar
  27. 27.
    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;15:571–80.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genomics. 2008;18:637–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Song IS, Lee do Y, Shin MH, Kim H, Ahn YG, Park I, Kim KH, et al. Pharmacogenetics meets metabolomics: discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition. PLoS One. 2012;7:e36637.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Kang HJ, Song IS, Shin HJ, Kim WY, Lee CH, Shim JC, Zhou HH, et al. Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population. Drug Metab Dispos. 2007;35:667–75.PubMedCrossRefGoogle Scholar
  31. 31.
    Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Lazar A, Grundemann D, Berkels R, Taubert D, Zimmermann T, Schomig E. Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet. 2003;48:226–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, Portman MA, et al. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics. 2010;20:687–99.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, Mulholland S, et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet. 2008;40:316–21.PubMedCrossRefGoogle Scholar
  35. 35.
    Tregouet DA, Konig IR, Erdmann J, Munteanu A, Braund PS, Hall AS, Grosshennig A, et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet. 2009;41:283–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Cui R, Okada Y, Jang SG, Ku JL, Park JG, Kamatani Y, Hosono N, et al. Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. Gut. 2011;60:799–805.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004;36:471–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet. 2003;35:341–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Komlosi K, Talian GC, Farago B, Magyari L, Cserep V, Kovacs B, Bene J, et al. No influence of SLC22A4 C6607T and RUNX1 G24658C genotypic variants on the circulating carnitine ester profile in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:61–6.PubMedGoogle Scholar
  40. 40.
    Ha Choi J, Wah Yee S, Kim MJ, Nguyen L, Ho Lee J, Kang JO, Hesselson S, et al. Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1. Pharmacogenet Genomics. 2009;19:770–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, Ramirez AH, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2013;93:186–94.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. 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. 2009;58:745–9.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, Mefford JA, et al. A common 5′-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther. 2011;90:674–84.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Chung JY, Cho SK, Kim TH, Kim KH, Jang GH, Kim CO, Park EM, et al. Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. Pharmacogenet Genomics. 2013;23:365–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Keller T, Egenberger B, Gorboulev V, Bernhard F, Uzelac Z, Gorbunov D, Wirth C, et al. The large extracellular loop of organic cation transporter 1 influences substrate affinity and is pivotal for oligomerization. J Biol Chem. 2011;286:37874–86.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Herraez E, Lozano E, Macias RI, Vaquero J, Bujanda L, Banales JM, Marin JJ, et al. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology. 2013;58:1065–73.PubMedCrossRefGoogle Scholar
  47. 47.
    Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S, Liloglou T, et al. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood. 2013;121:628–37.PubMedCrossRefGoogle Scholar
  48. 48.
    O’Brien VP, Bokelmann K, Ramirez J, Jobst K, Ratain MJ, Brockmoller J, Tzvetkov MV. 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;347:181–92.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Kim MH, Shin HJ, Lim SJ, Park JS, Lee SS, Song IS, Shin JG. Inter-individual variability in OCT1 expression and its relationship with OCT1 genotype in liver samples from a Korean population. Drug Metab Pharmacokinet. 2012;27:530–5.PubMedCrossRefGoogle Scholar
  50. 50.
    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;51:913–21.PubMedGoogle Scholar
  51. 51.
    Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43:1131–8.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, Pellikka N, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation. 2011;123:731–8.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Koeberl DD, Young SP, Gregersen NS, Vockley J, Smith WE, Benjamin Jr DK, An Y, et al. Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res. 2003;54:219–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Merinero B, Perez-Cerda C, Ruiz Sala P, Ferrer I, Garcia MJ, Martinez Pardo M, Belanger-Quintana A, et al. Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy. J Inherit Metab Dis. 2006;29:685.PubMedCrossRefGoogle Scholar
  55. 55.
    Fukuda T, Chidambaran V, Mizuno T, Venkatasubramanian R, Ngamprasertwong P, Olbrecht V, Esslinger HR, et al. OCT1 genetic variants influence the pharmacokinetics of morphine in children. Pharmacogenomics. 2013;14:1141–51.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Venkatasubramanian R, Fukuda T, Niu J, Mizuno T, Chidambaran V, Vinks AA, Sadhasivam S. ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children. Pharmacogenomics. 2014;15:1297–309.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83:273–80.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Christensen MM, Brasch-Andersen C, Green H, Nielsen F, Damkier P, Beck-Nielsen H, Brosen K. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics. 2011;21:837–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Christensen MM, Pedersen RS, Stage TB, Brasch-Andersen C, Nielsen F, Damkier P, Beck-Nielsen H, et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet Genomics. 2013;23:526–34.PubMedCrossRefGoogle Scholar
  60. 60.
    Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G, Hattersley AT, et al. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes. 2009;58:1434–9.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K, Ieiri I. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet. 2007;52:117–22.PubMedCrossRefGoogle Scholar
  62. 62.
    Gambineri A, Tomassoni F, Gasparini DI, Di Rocco A, Mantovani V, Pagotto U, Altieri P, 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:E204–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Jablonski KA, McAteer JB, de Bakker PI, Franks PW, Pollin TI, Hanson RL, Saxena R, 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;59:2672–81.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Klen J, Goricar K, Janez A, Dolzan V. The role of genetic factors and kidney and liver function in glycemic control in type 2 diabetes patients on long-term metformin and sulphonylurea cotreatment. Biomed Res Int. 2014;2014:934729.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64:1786–93.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Schweighofer N, Lerchbaum E, Trummer O, Schwetz V, Pieber T, Obermayer-Pietsch B. Metformin resistance alleles in polycystic ovary syndrome: pattern and association with glucose metabolism. Pharmacogenomics. 2014;15:305–17.PubMedCrossRefGoogle Scholar
  67. 67.
    Christensen M, Brasch-Andersen C, Green H. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c: corrigendum. Pharmacogenet Genimics. 2015;25:48–50.CrossRefGoogle Scholar
  68. 68.
    Groer C, Bruck S, Lai Y, Paulick A, Busemann A, Heidecke CD, Siegmund W, et al. LC-MS/MS-based quantification of clinically relevant intestinal uptake and efflux transporter proteins. J Pharm Biomed Anal. 2013;85:253–61.PubMedCrossRefGoogle Scholar
  69. 69.
    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;70:1851–60.PubMedCrossRefGoogle Scholar
  70. 70.
    Pernicova I, Korbonits M. Metformin-–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Davis R, Giacomini K, Yee SW, Jenkins G, McCarty C, Wilke R. PS1-10: response to metformin and genetic variants of organic cation and multidrug and toxin extrusion transporters. Clin Med Res. 2010;8:191.CrossRefGoogle Scholar
  73. 73.
    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;83:258–64.PubMedCrossRefGoogle Scholar
  74. 74.
    Nies AT, Schaeffeler E, van der Kuip H, Cascorbi I, Bruhn O, Kneba M, Pott C, et al. Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clin Cancer Res. 2014;20:985–94.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Swift B, Nebot N, Lee JK, Han T, Proctor WR, Thakker DR, Lang D, et al. Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos. 2013;41:1179–86.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009;15:6062–9.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Heise M, Lautem A, Knapstein J, Schattenberg JM, Hoppe-Lotichius M, Foltys D, Weiler N, et al. Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer. 2012;12:109.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Namisaki T, Schaeffeler E, Fukui H, Yoshiji H, Nakajima Y, Fritz P, Schwab M, et al. Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma. Drug Metab Dispos. 2014;42:2033–40.PubMedCrossRefGoogle Scholar
  79. 79.
    Schaeffeler E, Hellerbrand C, Nies AT, Winter S, Kruck S, Hofmann U, van der Kuip H, et al. DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. Genome Med. 2011;3:82.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler B, Romero IA, et al. Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol. 2012;83:805–14.PubMedCrossRefGoogle Scholar
  81. 81.
    Dos Santos Pereira JN, Tadjerpisheh S, Abed MA, Saadatmand AR, Weksler B, Romero IA, Couraud PO, 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;16:1247–58.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Rosenzweig P, Canal M, Patat A, Bergougnan L, Zieleniuk I, Bianchetti G. A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol. 2002;17:1–13.PubMedCrossRefGoogle Scholar
  83. 83.
    Wiesel FA, Alfredsson G, Ehrnebo M, Sedvall G. The pharmacokinetics of intravenous and oral sulpiride in healthy human subjects. Eur J Clin Pharmacol. 1980;17:385–91.PubMedCrossRefGoogle Scholar
  84. 84.
    Lin C-J, Tai Y, Huang M-T, Tsai Y-F, Hsu H-J, Tzen K-Y, Liou H-H. 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;114:717–27.PubMedCrossRefGoogle Scholar
  85. 85.
    Arimany-Nardi C, Montraveta A, Lee-Verges E, Puente XS, Koepsell H, Campo E, Colomer D, 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;15:363–71.PubMedCrossRefGoogle Scholar
  86. 86.
    Arimany-Nardi C, Errasti-Murugarren E, Minuesa G, Martinez-Picado J, Gorboulev V, Koepsell H, Pastor-Anglada M. Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors. Br J Pharmacol. 2014;171:3868–80.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of Debrisoquine in man. Lancet. 1977;2:584–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Choi MK, Song IS. Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos. 2012;33:170–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, Urban TJ, et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics. 2009;19:497–504.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Grun B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G, Haefeli WE, et al. Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin Pharmacol. 2013;76:787–96.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Reznichenko A, Sinkeler SJ, Snieder H, van den Born J, de Borst MH, Damman J, van Dijk MC, et al. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol Genomics. 2013;45:201–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstadt H, Massmann V, et al. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res. 2012;18:1101–8.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Lazar A, Zimmermann T, Koch W, Grundemann D, Schomig A, Kastrati A, Schomig E. Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clin Exp Hypertens. 2006;28:645–53.PubMedCrossRefGoogle Scholar
  94. 94.
    Grundemann D, Koster S, Kiefer N, Breidert T, Engelhardt M, Spitzenberger F, Obermuller N, et al. Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem. 1998;273:30915–20.PubMedCrossRefGoogle Scholar
  95. 95.
    Zolk O. Current understanding of the pharmacogenomics of metformin. Clin Pharmacol Ther. 2009;86:595–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J. 2013;15:581–8.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Ciarimboli G, Ludwig T, Lang D, Pavenstadt H, Koepsell H, Piechota HJ, Haier J, et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol. 2005;167:1477–84.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Filipski KK, Loos WJ, Verweij J, Sparreboom A. Interaction of Cisplatin with the human organic cation transporter 2. Clin Cancer Res. 2008;14:3875–80.PubMedCrossRefGoogle Scholar
  99. 99.
    Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstadt H, et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010;176:1169–80.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther. 2009;86:396–402.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Iwata K, Aizawa K, Kamitsu S, Jingami S, Fukunaga E, Yoshida M, Yoshimura M, et al. Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events. Clin Exp Nephrol. 2012;16:843–51.PubMedCrossRefGoogle Scholar
  102. 102.
    Tzvetkov MV, Behrens G, O’Brien VP, Hohloch K, Brockmoller J, Benohr P. Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms. Pharmacogenomics. 2011;12:1417–27.PubMedCrossRefGoogle Scholar
  103. 103.
    Lanvers-Kaminsky C, Sprowl JA, Malath I, Deuster D, Eveslage M, Schlatter E, Mathijssen RH, et al. Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity. Pharmacogenomics. 2015;16:323–32.PubMedCrossRefGoogle Scholar
  104. 104.
    Lazar A, Walitza S, Jetter A, Gerlach M, Warnke A, Herpertz-Dahlmann B, Grundemann D, et al. Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol. 2008;11:35–48.PubMedCrossRefGoogle Scholar
  105. 105.
    Fisher SA, Hampe J, Onnie CM, Daly MJ, Curley C, Purcell S, Sanderson J, et al. Direct or indirect association in a complex disease: the role of SLC22A4 and SLC22A5 functional variants in Crohn disease. Hum Mutat. 2006;27:778–85.PubMedCrossRefGoogle Scholar
  106. 106.
    Pochini L, Scalise M, Galluccio M, Pani G, Siminovitch KA, Indiveri C. The human OCTN1 (SLC22A4) reconstituted in liposomes catalyzes acetylcholine transport which is defective in the mutant L503F associated to the Crohn’s disease. Biochim Biophys Acta. 1818;2012:559–65.Google Scholar
  107. 107.
    Tahara H, Yee SW, Urban TJ, Hesselson S, Castro RA, Kawamoto M, Stryke D, et al. Functional genetic variation in the basal promoter of the organic cation/carnitine transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5). J Pharmacol Exp Ther. 2009;329:262–71.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Kawasaki Y, Kato Y, Sai Y, Tsuji A. Functional characterization of human organic cation transporter OCTN1 single nucleotide polymorphisms in the Japanese population. J Pharm Sci. 2004;93:2920–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Urban TJ, Gallagher RC, Brown C, Castro RA, Lagpacan LL, Brett CM, Taylor TR, et al. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol Pharmacol. 2006;70:1602–11.PubMedCrossRefGoogle Scholar
  110. 110.
    Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM, Green T, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet. 2000;66:1863–70.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z, Delmonte T, et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet. 2001;29:223–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Onnie C, Fisher SA, King K, Mirza M, Roberts R, Forbes A, Sanderson J, et al. Sequence variation, linkage disequilibrium and association with Crohn’s disease on chromosome 5q31. Genes Immun. 2006;7:359–65.PubMedCrossRefGoogle Scholar
  113. 113.
    Martinez A, Martin MC, Mendoza JL, Taxonera C, Diaz-Rubio M, de la Concha EG, Urcelay E. Association of the organic cation transporter OCTN genes with Crohn’s disease in the Spanish population. Eur J Hum Genet. 2006;14:222–6.PubMedCrossRefGoogle Scholar
  114. 114.
    Gazouli M, Mantzaris G, Archimandritis AJ, Nasioulas G, Anagnou NP. Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn’s disease. World J Gastroenterol. 2005;11:7525–30.PubMedCrossRefGoogle Scholar
  115. 115.
    Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Polymorphisms in the organic cation transporter genes SLC22A4 and SLC22A5 and Crohn’s disease in a New Zealand Caucasian cohort. Immunol Cell Biol. 2006;84:233–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Russell RK, Drummond HE, Nimmo ER, Anderson NH, Noble CL, Wilson DC, Gillett PM, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut. 2006;55:1114–23.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Babusukumar U, Wang T, McGuire E, Broeckel U, Kugathasan S. Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn’s disease. Am J Gastroenterol. 2006;101:1354–61.PubMedCrossRefGoogle Scholar
  118. 118.
    Palmieri O, Latiano A, Valvano R, D’Inca R, Vecchi M, Sturniolo GC, Saibeni S, et al. Variants of OCTN1-2 cation transporter genes are associated with both Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2006;23:497–506.PubMedCrossRefGoogle Scholar
  119. 119.
    Torok HP, Glas J, Tonenchi L, Lohse P, Muller-Myhsok B, Limbersky O, Neugebauer C, et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn’s disease. Gut. 2005;54:1421–7.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Cucchiara S, Latiano A, Palmieri O, Staiano AM, D’Inca R, Guariso G, Vieni G, et al. Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases. World J Gastroenterol. 2007;13:1221–9.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Lin Z, Nelson L, Franke A, Poritz L, Li TY, Wu R, Wang Y, et al. OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease. J Crohns Colitis. 2010;4:132–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Waller S, Tremelling M, Bredin F, Godfrey L, Howson J, Parkes M. Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut. 2006;55:809–14.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Xuan C, Zhang BB, Yang T, Deng KF, Li M, Tian RJ. Association between OCTN1/2 gene polymorphisms (1672C-T, 207G-C) and susceptibility of Crohn’s disease: a meta-analysis. Int J Colorectal Dis. 2012;27:11–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Li M, Gao X, Guo CC, Wu KC, Zhang X, Hu PJ. OCTN and CARD15 gene polymorphism in Chinese patients with inflammatory bowel disease. World J Gastroenterol. 2008;14:4923–7.PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Rubin GP, Hungin AP, Kelly PJ, Ling J. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther. 2000;14:1553–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Yao T, Matsui T, Hiwatashi N. Crohn’s disease in Japan: diagnostic criteria and epidemiology. Dis Colon Rectum. 2000;43:S85–93.PubMedCrossRefGoogle Scholar
  127. 127.
    Huff CD, Witherspoon DJ, Zhang Y, Gatenbee C, Denson LA, Kugathasan S, Hakonarson H, et al. Crohn’s disease and genetic hitchhiking at IBD5. Mol Biol Evol. 2012;29:101–11.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, Kagaya T, et al. Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharm Res. 2010;27:832–40.PubMedCrossRefGoogle Scholar
  129. 129.
    Fortin G, Yurchenko K, Collette C, Rubio M, Villani AC, Bitton A, Sarfati M, et al. L-carnitine, a diet component and organic cation transporter OCTN ligand, displays immunosuppressive properties and abrogates intestinal inflammation. Clin Exp Immunol. 2009;156:161–71.PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Santiago JL, Martinez A, de la Calle H, Fernandez-Arquero M, Figueredo MA, de la Concha EG, Urcelay E. Evidence for the association of the SLC22A4 and SLC22A5 genes with type 1 diabetes: a case control study. BMC Med Genet. 2006;7:54.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Martini M, Ferrara AM, Giachelia M, Panieri E, Siminovitch K, Galeotti T, Larocca LM, et al. Association of the OCTN1/1672T variant with increased risk for colorectal cancer in young individuals and ulcerative colitis patients. Inflamm Bowel Dis. 2012;18:439–48.PubMedCrossRefGoogle Scholar
  132. 132.
    Suchy J, Klujszo-Grabowska E, Kladny J, Cybulski C, Wokolorczyk D, Szymanska-Pasternak J, Kurzawski G, et al. Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk. BMC Cancer. 2008;8:112.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Shoji Y, Koizumi A, Kayo T, Ohata T, Takahashi T, Harada K, Takada G. Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q. Am J Hum Genet. 1998;63:101–8.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet. 1999;21:91–4.PubMedCrossRefGoogle Scholar
  135. 135.
    Lahjouji K, Mitchell GA, Qureshi IA. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol Genet Metab. 2001;73:287–97.PubMedCrossRefGoogle Scholar
  136. 136.
    Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res. 2007;24:1227–51.PubMedCrossRefGoogle Scholar
  137. 137.
    Li FY, El-Hattab AW, Bawle EV, Boles RG, Schmitt ES, Scaglia F, Wong LJ. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010;31:E1632–51.PubMedCrossRefGoogle Scholar
  138. 138.
    Nakamichi N, Shima H, Asano S, Ishimoto T, Sugiura T, Matsubara K, Kusuhara H, et al. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci. 2013;102:3407–17.PubMedCrossRefGoogle Scholar
  139. 139.
    Grube M, Meyer zu Schwabedissen HE, Prager D, Haney J, Moritz KU, Meissner K, Rosskopf D, et al. Uptake of cardiovascular drugs into the human heart: expression, regulation, and function of the carnitine transporter OCTN2 (SLC22A5). Circulation. 2006;113:1114–22.PubMedCrossRefGoogle Scholar
  140. 140.
    Kajiwara M, Terada T, Ogasawara K, Iwano J, Katsura T, Fukatsu A, Doi T, et al. Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. J Hum Genet. 2009;54:40–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB. Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010;298:F997–1005.PubMedCrossRefGoogle Scholar
  142. 142.
    Toyama K, Yonezawa A, Tsuda M, Masuda S, Yano I, Terada T, Osawa R, et al. Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients. Pharmacogenet Genomics. 2010;20:135–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Mladen Vassilev Tzvetkov
    • 1
    Email author
  • Nawar Dalila
    • 1
  • Frank Faltraco
    • 1
  1. 1.Institute of Clinical PharmacologyUniversity Medical Center GöttingenGöttingenGermany

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