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Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeutic Implications

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Organic Cation Transporters in the Central Nervous System

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 266))

Abstract

The gene products of the SLC22A gene family (hOCT1, hOCT2, and hOCT3) and of the SLC29A4 gene (hPMAT or hENT4) are all polyspecific organic cation transporters. Human OCTs (including hPMAT) are expressed in peripheral tissues such as small intestine, liver, and kidney involved in the pharmacokinetics of drugs. In the human brain, all four transporters are expressed at the blood-brain barrier (BBB), hOCT2 is additionally expressed in neurons, and hOCT3 and hPMAT in glia. More than 40% of the presently used drugs are organic cations. This chapter lists and discusses all known drugs acting as substrates or inhibitors of these four organic cation transporters, independently of whether the transporter is expressed in the central nervous system (CNS) or in peripheral tissues. Of interest is their involvement in drug absorption, distribution, and excretion as well as potential OCT-associated drug–drug interactions (DDIs), with a focus on drugs that act in the CNS.

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References

  • Agu R, MacDonald C, Cowley E, Shao D, Renton K, Clarke DB, Massoud E (2011) Differential expression of organic cation transporters in normal and polyps human nasal epithelium: implications for in vitro drug delivery studies. Int J Pharm 406:49–54

    Article  CAS  PubMed  Google Scholar 

  • Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CAS, Artursson P (2008) Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem 51:5932–5942

    Article  CAS  PubMed  Google Scholar 

  • Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952

    Article  CAS  PubMed  Google Scholar 

  • Amphoux A, Millan MJ, Cordi A, Bönisch H, Vialou V, Mannoury la Cour C, Dupuis DS, Giros B, Gautron S (2010) Inhibitory and facilitory actions of isocyanine derivatives at human and rat organic cation transporters 1, 2 and 3: a comparison to human alpha 1- and alpha 2-adrenoceptor subtypes. Eur J Pharmacol 634:1–9

    Article  CAS  PubMed  Google Scholar 

  • Arimany-Nardi C, Koepsell H, Pastor-Anglada M (2015) Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug-drug interactions. Pharmacogenomics J 15:473–487

    Article  CAS  PubMed  Google Scholar 

  • Barengolts E, Green SJ, Eisenberg Y, Akbar A, Reddivari B, Layden BT, Dugas L, Chlipala G (2018) Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease. PLoS One 13:e0194171

    Article  PubMed  PubMed Central  Google Scholar 

  • Bayer M, Kuçi Z, Schömig E, Gründemann D, Dittmann H, Handgretinger R, Bruchelt G (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

    Article  CAS  PubMed  Google Scholar 

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

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Belzer M, Morales M, Jagadish B, Mash EA, Wright SH (2013) Substratedependent ligand inhibition of the human organic cation transporter OCT2. J Pharmacol Exp Ther 346:300–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biermann J, Lang D, Gorboulev V, Koepsell H, Sindic A, Schröter R, Zvirbliene A, Pavenstädt H, Schlatter E, Ciarimboli G (2006) Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol 290:C1521–C1531

    Article  CAS  PubMed  Google Scholar 

  • Bönisch H (1978) Further studies on the extraneuronal uptake and metabolism of isoprenaline in the perfused rat heart. Naunyn Schmiedeberg’s Arch Pharmacol 303(2):121–131. https://doi.org/10.1007/BF00508057. PMID: 673019

    Article  Google Scholar 

  • Bönisch H (1980) Extraneuronal transport of catecholamines. Pharmacology 21:93–108. https://doi.org/10.1159/000137422

    Article  PubMed  Google Scholar 

  • Bönisch H, Rodrigues-Pereira E (1983) Uptake of 14C-tyramine and release of extravesicular 3H-noradrenaline in isolated perfused rabbit hearts. Naunyn Schmiedebergs Arch Pharmacol 323(3):233–244. https://doi.org/10.1007/BF00497669

    Article  PubMed  Google Scholar 

  • Bönisch H, Bryan LJ, Henseling M, O’Donnell SR, Stockmann P, Trendelenburg U (1985) The effect of various ions on uptake2 of catecholamines. Naunyn Schmiedebergs Arch Pharmacol 328:407–416. https://doi.org/10.1007/BF00692909

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Bowman MA, Vitela M, Clarke KM, Koek W, Daws LC (2020) Serotonin transporter and plasma membrane monoamine transporter are necessary for the antidepressant-like effects of ketamine in mice. Int J Mol Sci 21:7581. https://doi.org/10.3390/ijms21207581

    Article  CAS  PubMed Central  Google Scholar 

  • Burckhardt Y, Koepsell H (2013) Organic anion and cation transporters in renal elimination of drugs. In: Seldin and Giebisch’s the kidney: physiology and pathophysiology, vol 2, chapter 72, pp 2425–2456

    Google Scholar 

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

    Article  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 322:695–700

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, Li S, Xu L, Keshari KR, Lin MJ et al (2014) OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 111:9983–9988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen EC, Khuri N, Liang X, Stecula A, Chien HC, Yee SW, Huang Y, Sali A, Giacomini KM (2017) Discovery of competitive and noncompetitive ligands of the organic cation transporter 1 (OCT1; SLC22A1). J Med Chem 60:2685–2696

    Article  CAS  PubMed  Google Scholar 

  • Cho SK, Kim CO, Park ES, Chung JY (2014) Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers. Br J Clin Pharmacol 78:1426–1432. https://doi.org/10.1111/bcp.12476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarimboli G, Ludwig T, Lang D, Pavenstädt H, Koepsell H, Piechota HJ, Haier J, Jaehde U, Zisowsky J, Schlatter E (2005) Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 167:1477–1484. https://doi.org/10.1016/S0002-9440(10)61234-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarimboli G, Holle SK, Vollenbröcker B, Hagos Y, Reuter S, Burckhardt G, Bierer S, Herrmann E, Pavenstädt H, Rossi R et al (2011) New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2. Mol Pharm 8:270–279

    Article  CAS  PubMed  Google Scholar 

  • Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstädt H, Massmann V, Guckel D, Mathijssen RH, Yang W et al (2012) Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res 18:1101–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarimboli G, Schröter R, Neugebauer U, Vollenbröker B, Gabriëls G, Brzica H, Sabolić I, Pietig G, Pavenstädt H, Schlatter E, Edemir B (2013) Kidney transplantation down-regulates expression of organic cation transporters, which translocate β-blockers and fluoroquinolones. Mol Pharm 10:2370–2380

    Article  CAS  PubMed  Google Scholar 

  • Conchon Costa AC, Yamamoto PA, Rocha Lauretti G, de Lima Benzi JR, Zanelli CF, Barz V, Ciarimboli G, de Moraes NV (2020) Cetirizine reduces gabapentin plasma concentrations and effect: role of renal drug transporters for organic cations. J Clin Pharmacol 60:1076–1086

    Article  Google Scholar 

  • Dahlin A, Xia L, Kong W, Hevner R, Wang J (2007) Expression and immunolocalization of the plasma membrane monoamine transporter in the brain. Neuroscience 146:1193–1211. https://doi.org/10.1016/j.neuroscience.2007.01.072

    Article  CAS  PubMed  Google Scholar 

  • Dawed AY, Zhou K, van Leeuwen N, Mahajan A, Robertson N, Koivula R, Elders PJM, Rauh SP, Jones AG, Holl RW, Stingl JC, Franks PW, McCarthy MI, Leen’t Hart LM, Pearson ER (2019) Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: an IMI DIRECT study. Diabetes Care 42:1027–1033. https://doi.org/10.2337/dc18-2182

    Article  CAS  PubMed  Google Scholar 

  • Daws LC (2009) Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther 121:89–99. https://doi.org/10.1016/j.pharmthera.2008.10.004

    Article  CAS  PubMed  Google Scholar 

  • Diao L, Shu Y, Polli JE (2010) Uptake of pramipexole by human organic cation transporters. Mol Pharm 7:1342–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler B, Romero IA, Couraud PO, Pirmohamed M (2012) Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem Pharmacol 83:805–814

    Article  CAS  PubMed  Google Scholar 

  • Dos Santos Pereira JN, Tadjerpisheh S, Abu Abed M, Saadatmand AR, Weksler B, Romero IA, Couraud PO, Brockmöller J, Tzvetkov MV (2014) The poorly membrane permeable antipsychotic drugs amisulpride and sulpiride are substrates of the organic cation transporters from the SLC22 family. AAPS J 16:1247–1258

    Article  PubMed  PubMed Central  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

    Article  CAS  PubMed  Google Scholar 

  • Duan H, Wang J (2010) Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther 335:743–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan H, Hu T, Foti RS, Pan Y, Swaan PW, Wang J (2015) Potent and selective inhibition of plasma membrane monoamine transporter by HIV protease inhibitors. Drug Metab Dispos 43:1773–1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dujic T, Causevic A, Bego T, Malenica M, Velija-Asimi Z, Pearson ER, Semiz S (2016) Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med 33:511–514. https://doi.org/10.1111/dme.13040

    Article  CAS  PubMed  Google Scholar 

  • Eisenhofer G (2001) The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 91:35–62. https://doi.org/10.1016/s0163-7258(01)00144-9

    Article  CAS  PubMed  Google Scholar 

  • Ellawatty WEA, Masuo Y, Fujita KI, Yamazaki E, Ishida H, Arakawa H, Nakamichi N, Abdelwahed R, Sasaki Y, Kato Y (2018) Organic cation transporter 1 is responsible for hepatocellular uptake of the tyrosine kinase inhibitor pazopanib. Drug Metab Dispos 46:33–40

    Article  CAS  PubMed  Google Scholar 

  • Engel K, Wang J (2005) Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol 68:1397–1407

    Article  CAS  PubMed  Google Scholar 

  • Engel K, Zhou M, Wang J (2004) Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem 279:50042–50049. https://doi.org/10.1074/jbc.M407913200

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Filipski KK, Loos WJ, Verweij J, Sparreboom A (2008) Interaction of cisplatin with the human organic cation transporter 2. Clin Cancer Res 14:3875–3880

    Article  CAS  PubMed  Google Scholar 

  • Fraser-Spears R, Krause-Heuer AM, Basiouny M, Mayer FP, Manishimwe R, Wyatt NA, Dobrowolski JC, Roberts MP, Greguric I, Kumar N, Koek W, Sitte HH, Callaghan PD, Fraser BH, Daws LC (2019) Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter. Eur J Pharmacol 842:351–364

    Article  CAS  PubMed  Google Scholar 

  • Gasser PJ, Daws LC (2017) Extending the family: roles for uptake2 transporters in regulation of monoaminergic signaling. J Chem Neuroanat 83-84:107–108. https://doi.org/10.1016/j.jchemneu.2017.07.009

    Article  CAS  PubMed  Google Scholar 

  • Geier EG, Chen EC, Webb A, Papp AC, Yee SW, Sadee W, Giacomini KM (2013) Profiling solute carrier transporters in the human blood-brain barrier. Clin Pharmacol Ther 94:636–639. https://doi.org/10.1038/clpt.2013.175. Epub 2013 Sep 5

    Article  CAS  PubMed  Google Scholar 

  • Gessner A, König J, Fromm MF (2019) Clinical Aspects of Transporter-Mediated Drug-Drug Interactions. Clin Pharmacol Ther 105(6):1386–1394. https://doi.org/10.1002/cpt.1360. Epub 2019 Mar 18. PMID: 30648735

    Article  CAS  PubMed  Google Scholar 

  • Girardin F (2006) Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin Neurosci 8:311–321. https://doi.org/10.31887/DCNS.2006.8.3/fgirardin

    Article  PubMed Central  PubMed  Google Scholar 

  • Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881

    Article  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. https://doi.org/10.1124/mol.56.6.1254

    Article  CAS  PubMed  Google Scholar 

  • Grimm D, Lieb J, Weyer V, Vollmar J, Darstein F, Lautem A, Hoppe-Lotichius M, Koch S, Schad A, Schattenberg JM, Wörns MA, Weinmann A, Galle PR, Zimmermann T (2016) Organic cation transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer 16:94. https://doi.org/10.1186/s12885-016-2150-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gründemann D, Gorboulev V, Gambaryan S, Veyhl M (1994) Koepsell H (1994) drug excretion mediated by a new prototype of polyspecific transporter. Nature 372(6506):549–552. https://doi.org/10.1038/372549a0

    Article  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

    Article  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

    Article  PubMed  Google Scholar 

  • Gründemann D, Hahne C, Berkels R, Schömig 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

    Article  PubMed  Google Scholar 

  • Gupta S, Wulf G, Henjakovic M, Koepsell H, Burckhardt G, Hagos Y (2012) Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther 341:16–23

    Article  CAS  PubMed  Google Scholar 

  • Haenisch B, Bönisch H (2010) Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics. Naunyn Schmiedebergs Arch Pharmacol 57:33–39

    Article  Google Scholar 

  • Haenisch B, Hiemke C, Bönisch H (2011) Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters. Psychopharmacology (Berl) 217:289–295

    Article  CAS  Google Scholar 

  • Haenisch B, Drescher E, Thiemer L, Xin H, Giros B, Gautron S, Bönisch H (2012) Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol 385:1017–1023

    Article  CAS  PubMed  Google Scholar 

  • Han TK, Everett RS, Proctor WR, Ng CM, Costales CL, Brouwer KL, Thakker DR (2013) Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol 84:182–189. https://doi.org/10.1124/mol.112.084517

    Article  CAS  PubMed  Google Scholar 

  • Hara K, Yanagihara N, Minami K, Ueno S, Toyohira Y, Sata T, Kawamura M, Brüss M, Bönisch H, Shigematsu A, Izumi F (1998) Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site. Naunyn Schmiedebergs Arch Pharmacol 358:328–333. https://doi.org/10.1007/pl00005261

    Article  CAS  PubMed  Google Scholar 

  • Hasannejad H, Takeda M, Narikawa S, Huang X-L, Enomoto A, Taki K, Niwa T, Jung SH, Onozato ML, Tojo A, Endou H (2004) Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. Eur J Pharmacol 499(1–2):45–51. https://doi.org/10.1016/j.ejphar.2004.07.098. PMID: 15363950

    Article  CAS  PubMed  Google Scholar 

  • Hasannejad H, Takeda M, Narikawa S, Huang X-L, Enomoto A, Taki K, Niwa T, Jung SH, Onozato ML, Tojo A et al (2009) Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. Eur J Pharmacol 499:45–51

    Article  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hendley ED, Taylor KM, Snyder SH (1970) 3H-normetanephrine uptake in rat brain slices. Relationship to extraneuronal accumulation of norepinephrine. Eur J Pharmacol 12:167–179. https://doi.org/10.1016/0014-2999(70)90062-2

    Article  CAS  PubMed  Google Scholar 

  • Hendrickx R, Johansson JG, Lohmann C, Jenvert RM, Blomgren A, Börjesson L, Gustavsson L (2013) Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem 56:7232–7242

    Article  CAS  PubMed  Google Scholar 

  • Ho HT, Dahlin A, Wang J (2012) Expression profiling of solute carrier gene families at the blood-CSF barrier. Front Pharmacol 3:154. https://doi.org/10.3389/fphar.2012.00154. eCollection 2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imamura Y, Murayama N, Okudaira N, Kurihara A, Okazaki O, Izumi T, Inoue K, Yuasa H, Kusuhara H, Sugiyama Y (2011) Prediction of fluoroquinoloneinduced elevation in serum creatinine levels: a case of drug-endogenous substance interaction involving the inhibition of renal secretion. Clin Pharmacol Ther 89:81–88

    Article  CAS  PubMed  Google Scholar 

  • Ishiguro N, Saito A, Yokoyama K, Morikawa M, Igarashi T, Tamai I (2005) Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metab Dispos 33:495–499. https://doi.org/10.1124/dmd.104.002519. Epub 2005 Jan 7

    Article  CAS  PubMed  Google Scholar 

  • Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, Sugiyama Y (2012) Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther 340:393–403

    Article  CAS  PubMed  Google Scholar 

  • Ivanyuk A, Livio F, Biollaz J, Buclin T (2017) Renal drug transporters and drug interactions. Clin Pharmacokinet 56:825–892. https://doi.org/10.1007/s40262-017-0506-8

    Article  CAS  PubMed  Google Scholar 

  • Iversen LL (1965) The uptake of catechol amines at high perfusion concentrations in the rat isolated heart: a novel catechol amine uptake process. Br J Pharmacol Chemother 25:18–33. https://doi.org/10.1111/j.1476-5381.1965.tb01753.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iversen LL (1971) Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 41(4):571–591. https://doi.org/10.1111/j.1476-5381.1971.tb07066.x. PMID: 4397129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iversen LL (1973) Catecholamine uptake processes. Br Med Bull 29:130–135. https://doi.org/10.1093/oxfordjournals.bmb.a070982

    Article  CAS  PubMed  Google Scholar 

  • Iversen LL, Salt PJ, Wilson HA (1972) Inhibition of catecholamine uptake in the isolated rat heart by haloalkylamines related to phenoxybenzamine. Br J Pharmacol 46:647–657. https://doi.org/10.1111/j.1476-5381.1972.tb06890.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen O, Rafehi M, Gebauer L, Brockmöller J (2021) Cellular uptake of psychostimulants – are high- and low-affinity organic cation transporters drug traffickers? Front Pharmacol 11:609811. https://doi.org/10.3389/fphar.2020.609811. eCollection 2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J, Stellbrink HJ, Faetkenheuer G, Taubert D (2008) Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 36:1616–1623

    Article  CAS  PubMed  Google Scholar 

  • Jung HW, Choi MS, Kim KH, Park SH, Yeon KK, Lee JH, Koh KC, Paik SW, Yoo BC (2009) Virologic response to adefovir dipivoxil monotherapy is not durable in HBeAg-positive, lamivudine-resistant chronic hepatitis B patients. Korean J Hepatol 15(1):52–58. https://doi.org/10.3350/kjhep.2009.15.1.52. PMID: 19346785

    Article  PubMed  Google Scholar 

  • Jung N, Lehmann C, Rubbert A, Schömig E, Fätkenheuer G, Hartmann P, Taubert D (2013) Organic cation transporters OCT1 and OCT2 determine the accumulation of lamivudine in CD4 cells of HIV-infected patients. Infection 41:379–385. https://doi.org/10.1007/s15010-012-0308-8. Epub 2012 Aug 9

    Article  CAS  PubMed  Google Scholar 

  • Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, Ganapathy V (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. https://doi.org/10.1074/jbc.273.26.15971

    Article  CAS  PubMed  Google Scholar 

  • Keller T, Elfeber M, Gorboulev V, Reiländer H, Koepsell H (2005) Purification and functional reconstitution of the rat organic cation transporter OCT1. Biochemistry 44:12253–12263. https://doi.org/10.1021/bi050676c

    Article  CAS  PubMed  Google Scholar 

  • Kido Y, Matsson P, Giacomini KM (2011) Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem 54:4548–4558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kikuchi R, Lao Y, Bow DA, Chiou WJ, Andracki ME, Carr RA, Voorman RL, De Morais SM (2013) Prediction of clinical drug-drug interactions of veliparib (ABT-888) with human renal transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K). J Pharm Sci 102:4426–4432

    Article  CAS  PubMed  Google Scholar 

  • Kim A, Chung I, Yoon SH, Yu KS, Lim KS, Cho JY, Lee H, Jang IJ, Chung JY (2014) Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos 42:1174–1179. https://doi.org/10.1124/dmd.113.055616. Epub 2014 Apr 24

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H (2011) Substrate recognition and translocation by polyspecific organic cation transporters. Biol Chem 392:95–101. https://doi.org/10.1515/BC.2011.009

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H (2015) Role of organic cation transporters in drug-drug interaction. Expert Opin Drug Metab Toxicol 11:1619–1633. https://doi.org/10.1517/17425255.2015.1069274. Epub 2015 Jul 24

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H (2019) Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs. Biol Chem 400:195–207. https://doi.org/10.1515/hsz-2018-0191

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H (2020) Organic cation transporters in health and disease. Pharmacol Rev 72:253–319

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H, Schmitt BM, Gorboulev V (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150:36–90. https://doi.org/10.1007/s10254-003-0017-x. Epub 2003 Jun 25

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Kummer W, Wiegand S, Akinci S, Schinkel AH, Wess J, Koepsell H, Haberberger RV, Lips KS (2006) Role of acetylcholine and muscarinic receptors in serotonin-induced bronchoconstriction in the mouse. J Mol Neurosci 30:67–68. https://doi.org/10.1385/JMN:30:1:67

    Article  CAS  PubMed  Google Scholar 

  • Lashford LS, Moyes J, Ott R, Fielding S, Babich J, Mellors S, Gordon I, Evans K, Kemshead JT (1988) The biodistribution and pharmacokinetics of meta-iodobenzylguanidine in childhood neuroblastoma. Eur J Nucl Med 13:574–577. https://doi.org/10.1007/BF02574771

    Article  CAS  PubMed  Google Scholar 

  • Lepist EI, Zhang X, Hao J, Huang J, Kosaka A, Birkus G, Murray BP, Bannister R, Cihlar T, Huang Y et al (2014) Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int 86:350–357

    Article  CAS  PubMed  PubMed Central  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(2):262–272. https://doi.org/10.1002/jps.10534. PMID: 14705184

    Article  CAS  PubMed  Google Scholar 

  • Li X, Sun X, Chen J, Lu Y, Zhang Y, Wang C, Li J, Zhang Q, Zhao D, Chen X (2015) Investigation of the role of organic cation transporter 2 (OCT2) in the renal transport of guanfacine, a selective alpha2A-adrenoreceptor agonist. Xenobiotica 45(1):88–94. https://doi.org/10.3109/00498254.2014.949904. Epub 2014 Aug 13. PMID: 25115365

  • Li L, Weng Y, Wang W, Bai M, Lei H, Zhou H, Jiang H (2017) Multiple organic cation transporters contribute to the renal transport of sulpiride. Biopharm Drug Dispos 38:526–534

    Article  CAS  PubMed  Google Scholar 

  • Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY, Liou HH (2010) 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 114:717–727. https://doi.org/10.1111/j.1471-4159.2010.06801.x. Epub 2010 May 6

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Liu X (2019) Contributions of drug transporters to blood-brain barriers. Adv Exp Med Biol 1141:407–466. https://doi.org/10.1007/978-981-13-7647-4_9

    Article  CAS  PubMed  Google Scholar 

  • López Quiñones AJ, Wagner DJ, Wang J (2020) Characterization of meta-Iodobenzylguanidine (mIBG) transport by polyspecific organic cation transporters: implication for mIBG therapy. Mol Pharmacol 98:109–119

    Article  PubMed  PubMed Central  Google Scholar 

  • Lozano E, Herraez E, Briz O, Robledo VS, Hernandez-Iglesias J, Gonzalez-Hernandez A, Marin JJ (2013) Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int 2013:692071. https://doi.org/10.1155/2013/692071. Epub 2013 Jul 31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mack F, Bönisch H (1979) Dissociation constants and lipophilicity of catecholamines and related compounds. Naunyn Schmiedebergs Arch Pharmacol 310:1–9. https://doi.org/10.1007/BF00499868

    Article  CAS  PubMed  Google Scholar 

  • Massmann V, Edemir B, Schlatter E, Al-Monajjed R, Harrach S, Klassen P, Holle SK, Sindic A, Dobrivojevic M, Pavenstädt H et al (2014) The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. Pflugers Arch 466:517–527

    Article  CAS  PubMed  Google Scholar 

  • Mayer FP, Schmid D, Owens WA, Gould GG, Apuschkin M, Kudlacek O, Salzer I, Boehm S, Chiba P, Williams PH, Wu HH, Gether U, Koek W, Daws LC, Sitte HH (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408–2417. https://doi.org/10.1038/s41386-018-0053-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer MJ, Seitz T, Brockmöller J, Tzvetkov MV (2017) Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine. PLoS One 12:e0189521. https://doi.org/10.1371/journal.pone.0189521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer MJ, Neumann VE, Friesacher HR, Zdrazil B, Brockmöller J, Tzvetkov MV (2019) Opioids as substrates and inhibitors of the genetically highly variable organic cation transporter OCT1. J Med Chem 62:9890–9905. https://doi.org/10.1021/acs.jmedchem.9b01301. Epub 2019 Nov 4

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, Clotet B, Pastor-Anglada M, Koepsell H, Martinez-Picado J (2009) Transport of lamivudine [(−)-b-L-29,39-dideoxy-39-thiacytidine] 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

    Article  CAS  PubMed  Google Scholar 

  • Minuesa G, Huber-Ruano I, Pastor-Anglada M, Koepsell H, Clotet B, Martinez-Picado J (2011) Drug uptake transporters in antiretroviral therapy. Pharmacol Ther 132:268–279

    Article  CAS  PubMed  Google Scholar 

  • Misaka S, Knop J, Singer K, Hoier E, Keiser M, Müller F, Glaeser H, König J, Fromm MF (2016) The nonmetabolized b-blocker nadolol is a substrate of OCT1, OCT2, MATE1, MATE2-K, and P-glycoprotein, but not of OATP1B1 and OATP1B3. Mol Pharm 13:512–519

    Article  CAS  PubMed  Google Scholar 

  • Miura Y, Yoshikawa T, Naganuma F, Nakamura T, Iida T, Kárpáti A, Matsuzawa T, Mogi A, Harada R, Yanai K (2017) Characterization of murine polyspecific monoamine transporters. FEBS Open Bio 7:237–248. https://doi.org/10.1002/2211-5463.12183. eCollection 2017 Feb

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrow CJ, Ghattas M, Smith C, Bönisch H, Bryce RA, Hickinson DM, Green TP, Dive C (2010) Src family kinase inhibitor Saracatinib (AZD0530) impairs oxaliplatin uptake in colorectal cancer cells and blocks organic cation transporters. Cancer Res 70:5931–5941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moss DM, Liptrott NJ, Curley P, Siccardi M, Back DJ, Owen A (2013) Rilpivirine inhibits drug transporters ABCB1, SLC22A1, and SLC22A2 in vitro. Antimicrob Agents Chemother 57:5612–5618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motohashi H, Uwai Y, Hiramoto K, Okuda M, Inui K (2004) Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Eur J Pharmacol 503:25–30

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Müller J, Keiser M, Drozdzik M, Oswald S (2017) Expression, regulation and function of intestinal drug transporters: an update. Biol Chem 398:175–192. https://doi.org/10.1515/hsz-2016-0259

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, Keppler D, Schwab M, Schaeffeler E (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. https://doi.org/10.1002/hep.23103

    Article  CAS  PubMed  Google Scholar 

  • Nies AT, Hofmann U, Resch C, Schaeffeler E, Rius M, Schwab M (2011) Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PLoS One 6:e22163

    Article  CAS  PubMed  PubMed Central  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. https://doi.org/10.2133/dmpk.20.452

    Article  CAS  PubMed  Google Scholar 

  • Okuda M, Saito H, Urakami Y, Takano M, Inui K (1996) cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun 224:500–507. https://doi.org/10.1006/bbrc.1996.1056

    Article  CAS  PubMed  Google Scholar 

  • Okura T, Kato S, Takano Y, Sato T, Yamashita A, Morimoto R, Ohtsuki S, Terasaki T, Deguchi Y (2011) Functional characterization of rat plasma membrane monoamine transporter in the blood-brain and blood-cerebrospinal fluid barriers. J Pharm Sci 100(9):3924–3938. https://doi.org/10.1002/jps.22594. PMID: 21538354

    Article  CAS  PubMed  Google Scholar 

  • Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354

    Article  CAS  PubMed  Google Scholar 

  • Pan G (2019) Roles of hepatic drug transporters in drug disposition and liver toxicity. Adv Exp Med Biol 1141:293–340. https://doi.org/10.1007/978-981-13-7647-4_6

    Article  CAS  PubMed  Google Scholar 

  • Pan X, Wang L, Gründemann D, Sweet DH (2013) Interaction of ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy. Antimicrob Agents Chemother 57:5053–5059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prasad B, Johnson K, Billington S, Lee C, Chung GW, Brown CD, Kelly EJ, Himmelfarb J, Unadkat JD (2016) Abundance of drug transporters in the human kidney cortex as quantified by quantitative targeted proteomics. Drug Metab Dispos 44:1920–1924. https://doi.org/10.1124/dmd.116.072066. Epub 2016 Sep 12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Russ H, Gliese M, Sonna J, Schömig E (1992) The extraneuronal transport mechanism for noradrenaline (uptake2) avidly transports 1-methyl-4-phenylpyridinium (MPP+). Naunyn Schmiedebergs Arch Pharmacol 346:158–165. https://doi.org/10.1007/BF00165297

    Article  CAS  PubMed  Google Scholar 

  • Russ H, Sonna J, Keppler K, Baunach S, Schömig E (1993) Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport. Naunyn Schmiedebergs Arch Pharmacol 348:458–465. https://doi.org/10.1007/BF00173203

    Article  CAS  PubMed  Google Scholar 

  • Russ H, Staust K, Martel F, Gliese M, Schomig E (1996) The extraneuronal transporter for monoamine transmitters exists in cells derived from human central nervous system glia. Eur J Neurosci 8:1256–1264

    Article  CAS  PubMed  Google Scholar 

  • Saidijam M, Karimi Dermani F, Sohrabi S, Patching SG (2018) Efflux proteins at the blood-brain barrier: review and bioinformatics analysis. Xenobiotica 48:506–532. https://doi.org/10.1080/00498254.2017.1328148. Epub 2017 May 30

    Article  CAS  PubMed  Google Scholar 

  • Sala-Rabanal M, Li DC, Dake GR, Kurata HT, Inyushin M, Skatchkov SN, Nichols CG (2013) Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm 10:1450–1458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salomon JJ, Hagos Y, Petzke S, Kühne A, Gausterer JC, Hosoya K, Ehrhardt C (2015) Beta-2 adrenergic agonists are substrates and inhibitors of human organic cation transporter 1. Mol Pharm 12:2633–2641

    Article  CAS  PubMed  Google Scholar 

  • Salt PJ (1972) Inhibition of noradrenaline uptake 2 in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines. Eur J Pharmacol 20(3):329–340. https://doi.org/10.1016/0014-2999(72)90194-x

    Article  CAS  PubMed  Google Scholar 

  • Sandoval PJ, Zorn KM, Clark AM, Ekins S, Wright SH (2018) Assessment of substrate-dependent ligand interactions at the organic cation transporter OCT2 using six model substrates. Mol Pharmacol 94:1057–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schömig E, Schönfeld CL (1990) Extraneuronal noradrenaline transport (uptake2) in a human cell line (Caki-1 cells). Naunyn Schmiedebergs Arch Pharmacol 341:404–410. https://doi.org/10.1007/BF00176331

    Article  PubMed  Google Scholar 

  • Sekhar GN, Georgian AR, Sanderson L, Vizcay-Barrena G, Brown RC, Muresan P, Fleck RA, Thomas SA (2017) Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB). PLoS One 12:e0173474. https://doi.org/10.1371/journal.pone.0173474. eCollection 2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekhar GN, Fleckney AL, Boyanova ST, Rupawala H, Lo R, Wang H, Farag DB, Rahman KM, Broadstock M, Reeves S, Thomas SA (2019) Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer's disease. Fluids Barriers CNS 16:38. https://doi.org/10.1186/s12987-019-0158-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Severance AC, Sandoval PJ, Wright SH (2017) Correlation between apparent substrate affinity and OCT2 transport turnover. J Pharmacol Exp Ther 362:405–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shnitsar V, Eckardt R, Gupta S, Grottker J, Müller GA, Koepsell H, Burckhardt G, Hagos Y (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

    Article  CAS  PubMed  Google Scholar 

  • Solbach TF, Grube M, Fromm MF, Zolk O (2011) Organic cation transporter 3: expression in failing and nonfailing human heart and functional characterization. J Cardiovasc Pharmacol 58:409–417

    Article  CAS  PubMed  Google Scholar 

  • Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, Janke LJ, Cavaletti G, Shields AF, Sparreboom A (2013) Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A 110:11199–11204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stachon A, Schlatter E, Hohage H (1996) Dynamic monitoring of organic cation transport processes by fluorescence measurements in LLC-PK1 cells. Cell Physiol Biochem 6:72–81. https://doi.org/10.1159/000154796

    Article  CAS  Google Scholar 

  • Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP (2015) Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy. Pediatr Blood Cancer 62:5–11. https://doi.org/10.1002/pbc.25200. Epub 2014 Aug 30

    Article  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

    Article  CAS  PubMed  Google Scholar 

  • Sun S, Wang K, Lei H, Li L, Tu M, Zeng S, Zhou H, Jiang H (2014) Inhibition of organic cation transporter 2 and 3 may be involved in the mechanism of the antidepressant-like action of berberine. Prog Neuropsychopharmacol Biol Psychiatry 49:1–6

    Article  CAS  PubMed  Google Scholar 

  • Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-brain barrier: from physiology to disease and back. Physiol Rev 99:21–78. https://doi.org/10.1152/physrev.00050.2017

    Article  CAS  PubMed  Google Scholar 

  • Sweet DH (2021) Organic cation transporter expression and function in the CNS. Handb Exp Pharmacol. https://doi.org/10.1007/164_2021_463

  • Swift B, Nebot N, Lee JK, Han T, Proctor WR, Thakker DR, Lang D, Radtke M, Gnoth MJ, Brouwer KL (2013) Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos 41:1179–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tahara H, Kusuhara H, Endou H, Koepsell H, Imaoka T, Fuse E, Sugiyama Y (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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Te Brake LH, van den Heuvel JJ, Buaben AO, van Crevel R, Bilos A, Russel FG, Aarnoutse RE, Koenderink JB (2016) Moxifloxacin is a potent in vitro inhibitor of OCT- and MATE-mediated transport of metformin and ethambutol. Antimicrob Agents Chemother 60:7105–7114

    Article  Google Scholar 

  • Thévenod F, Ciarimboli G, Leistner M, Wolff NA, Lee WK, Schatz I, Keller T, Al-Monajjed R, Gorboulev V, Koepsell H (2013) Substrate- and cell contact-dependent inhibitor affinity of human organic cation transporter 2: studies with two classical organic cation substrates and the novel substrate cd21. Mol Pharm 10:3045–3056

    Article  PubMed  Google Scholar 

  • Trendelenburg U (1978) Extraneuronal uptake and metabolism of catecholamines as a site of loss. Life Sci 22:1217–1222. https://doi.org/10.1016/0024-3205(78)90089-9

    Article  CAS  PubMed  Google Scholar 

  • Trendelenburg U (1989) The uptake and metabolism of 3H-catecholamines in rat cerebral cortex slices. Naunyn Schmiedebergs Arch Pharmacol 339:293–297. https://doi.org/10.1007/BF00173580

    Article  CAS  PubMed  Google Scholar 

  • Tzvetkov MV, Saadatmand AR, Lötsch J, Tegeder I, Stingl JC, Brockmöller J (2011) Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin Pharmacol Ther 90(1):143–150. https://doi.org/10.1038/clpt.2011.56. Epub 2011 May 11. PMID: 21562485

    Article  CAS  PubMed  Google Scholar 

  • Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmöller J (2013) Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol 86:666–678. https://doi.org/10.1016/j.bcp.2013.06.019. Epub 2013 Jul 5

    Article  CAS  PubMed  Google Scholar 

  • Tzvetkov MV, Matthaei J, Pojar S, Faltraco F, Vogler S, Prukop T, Seitz T, Brockmöller J (2018) Increased systemic exposure and stronger cardiovascular and metabolic adverse reactions to fenoterol in individuals with heritable OCT1 deficiency. Clin Pharmacol Ther 103:868–878

    Article  CAS  PubMed  Google Scholar 

  • Umehara K-I, Iwatsubo T, Noguchi K, Kamimura H (2007) Comparison of the kinetic characteristics of inhibitory effects exerted by biguanides and H2-blockers on human and rat organic cation transporter-mediated transport: insight into the development of drug candidates. Xenobiotica 37:618–634

    Article  CAS  PubMed  Google Scholar 

  • Umehara K-I, 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

    Article  CAS  PubMed  Google Scholar 

  • Urakami Y, Okuda M, Masuda S, Saito H, Inui KI (1998) Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther 287:800–8005

    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

    Article  CAS  PubMed  Google Scholar 

  • Visentin M, Torozi A, Gai Z, Häusler S, Li C, Hiller C, Schraml PH, Moch H, Kullak-Ublick GA (2018) Fluorocholine transport mediated by the organic cation transporter 2 (OCT2, SLC22A2): implication for imaging of kidney tumors. Drug Metab Dispos 46:1129–1136

    Article  CAS  PubMed  Google Scholar 

  • Volk C, Gorboulev V, Kotzsch A, Müller 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. https://doi.org/10.1124/mol.109.054783. Epub 2009 May 12

    Article  CAS  PubMed  Google Scholar 

  • Wagner DJ, Sager JE, Duan H, Isoherranen N, Wang J (2017) Interaction and transport of methamphetamine and its primary metabolites by organic cation and multidrug and toxin extrusion transporters. Drug Metab Dispos 45:770–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J (2016) The plasma membrane monoamine transporter (PMAT): structure, function, and role in organic cation disposition. Clin Pharmacol Ther 100:489–499. https://doi.org/10.1002/cpt.442. Epub 2016 Sep 19

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Sun S, Li L, Tu M, Jiang H (2014) Involvement of organic cation transporter 2 inhibition in potential mechanisms of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry 53:90–98

    Article  CAS  PubMed  Google Scholar 

  • Wenge B, Bönisch H (2009) Interference of the noradrenergic neurotoxin DSP4 with neuronal and nonneuronal monoamine transporters. Naunyn Schmiedebergs Arch Pharmacol 380:523–529

    Article  CAS  PubMed  Google Scholar 

  • Wenge B, Geyer J, Bönisch H (2011) Oxybutynin and trospium are substrates of the human organic cation transporters. Naunyn Schmiedebergs Arch Pharmacol 383:203–208

    Article  CAS  PubMed  Google Scholar 

  • Wilson VG, Grohmann M, Trendelenburg U (1988) The uptake and O-methylation of 3H-(+/−)-isoprenaline in rat cerebral cortex slices. Naunyn Schmiedebergs Arch Pharmacol 337:397–405. https://doi.org/10.1007/BF00169530

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776–32786

    Article  CAS  PubMed  Google Scholar 

  • Xia L, Engel K, Zhou M, Wang J (2007) Membrane localization and pH-dependent transport of a newly cloned organic cation transporter (PMAT) in kidney cells. Am J Physiol Renal Physiol 292:F682–F690. https://doi.org/10.1152/ajprenal.00302.2006. Epub 2006 Oct 3

    Article  CAS  PubMed  Google Scholar 

  • Xia L, Zhou M, Kalhorn TF, Ho HT, Wang J (2009) Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity. Am J Physiol Renal Physiol 296:F1307–F1313. https://doi.org/10.1152/ajprenal.00046.2009. Epub 2009 Apr 8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xue Y, Ma C, Hanna I, Pan G (2019) Intestinal transporter-associated drug absorption and toxicity. Adv Exp Med Biol 1141:1361–1405. https://doi.org/10.1007/978-981-13-7647-4_8

    Article  CAS  Google Scholar 

  • Yang X, Han L (2019) Roles of renal drug transporter in drug disposition and renal toxicity. Adv Exp Med Biol 1141:341–360. https://doi.org/10.1007/978-981-13-7647-4_7

    Article  CAS  PubMed  Google Scholar 

  • Yin J, Wang J (2016) Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 6(5):363–373. https://doi.org/10.1016/j.apsb.2016.07.013. Epub 2016 Aug 9. PMID: 27709005

    Article  PubMed  PubMed Central  Google Scholar 

  • Yin J, Duan H, Shirasaka Y, Prasad B, Wang J (2015) Atenolol renal secretion is mediated by human organic cation transporter 2 and multidrug and toxin extrusion proteins. Drug Metab Dispos 2015(43):1872–1881

    Article  Google Scholar 

  • Yokoo S, Masuda S, Yonezawa A, Terada T, Katsura T, Inui K-I (2008) Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer. Drug Metab Dispos 36:2299–2306. https://doi.org/10.1124/dmd.108.023168

    Article  CAS  PubMed  Google Scholar 

  • Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K (2006) Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 319:879–886. https://doi.org/10.1124/jpet.106.110346. Epub 2006 Aug 16

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa T, Yanai K (2017) Histamine clearance through polyspecific transporters in the brain. Handb Exp Pharmacol 241:173–187. https://doi.org/10.1007/164_2016_13

    Article  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

    Article  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, Chen Y, Komori T, Gray JW, Chen X et al (2006) Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 66:8847–8857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Xia L, Wang J (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 35:1956–1962

    Article  CAS  PubMed  Google Scholar 

  • Zhou M, Duan H, Engel K, Xia L, Wang J (2010) Adenosine transport by plasma membrane monoamine transporter: reinvestigation and comparison with organic cations. Drug Metab Dispos 38:1798–1805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou S, Zeng S, Shu Y (2021) Drug-drug interactions at organic cation transporter 1. Front Pharmacol 12:628705. https://doi.org/10.3389/fphar.2021.628705. eCollection 2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu H-J, Appel DI, Gründemann D, Markowitz JS (2010) Interaction of organic cation transporter 3 (SLC22A3) and amphetamine. J Neurochem 114(1):142–149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zolk O, Solbach TF, Konig J, Fromm MF (2009) Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2). Naunyn Schmiedebergs Arch Pharmacol 379:337–348

    Article  CAS  PubMed  Google Scholar 

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  1. Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany

    Heinz Bönisch

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  1. Heinz Bönisch
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Correspondence to Heinz Bönisch .

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  1. Departments of Cellular and Integrative Physiology, and Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA

    Lynette C. Daws

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Bönisch, H. (2021). Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeutic Implications. In: Daws, L.C. (eds) Organic Cation Transporters in the Central Nervous System. Handbook of Experimental Pharmacology, vol 266. Springer, Cham. https://doi.org/10.1007/164_2021_516

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