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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1141))

Abstract

Solute carrier (SLC) family transporters utilize an electrochemical potential difference or an ion gradient generated by primary active transporters for transporting their substrates across biological membranes. These transporters are categorized as facilitated transporters or secondary active transporters. More than 300 SLC transporters have been identified. SLC transporters related to drug transport mainly include SLC21 gene subfamily (organic anion-transporting polypeptides, OATPs), SLC22A gene subfamily (organic anion transporters, OATs; organic cation transporters, OCTs; or organic cation/carnitine transporters, OCTNs), SLC15A gene subfamily (peptide transporters, PEPTs), and SLC47A gene subfamily (multidrug and toxin extrusion, MATEs). In general, OCTs transport organic cations, OATPs transport large and fairly hydrophobic organic anions, OATs transport the smaller and more hydrophilic organic anions, and PEPTs are responsible for the uptake of di-/tripeptides and peptide-like drugs. MATEs are responsible for efflux of organic cations. These transporters also transport some endogenous substances, indicating that the dysfunction of SLCs not only disrupts homeostasis but also largely impacts on the disposition of their substrate drugs. This chapter will discuss these SLC family transporters, with an emphasis on tissue distribution, substrate specificity, transporter physiology, and clinical significance.

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References

  • Abe T, Unno M, Onogawa T, Tokui A, Kondo TN, Nakagomi R et al (2001) LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 120:1689–1699

    Article  CAS  PubMed  Google Scholar 

  • Agu R, Cowley E, Shao D, Mac Donald C, Kirkpatrick D, Renton K et al (2011) Proton-coupled oligopeptide transporter (POT) family expression in human nasal epithelium and their drug transport potential. Mol Pharm 8:664–672

    Article  CAS  PubMed  Google Scholar 

  • Ahn SY, Nigam SK (2009) Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol Pharmacol 76:481–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahn SY, Jamshidi N, Mo ML, Wu W, Eraly SA, Dnyanmote A et al (2011) Linkage of organic anion transporter-1 to metabolic pathways through integrated “omics”-driven network and functional analysis. J Biol Chem 286:31522–31531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akamine Y, Miura M, Komori H, Saito S, Kusuhara H, Tamai I et al (2014) Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers. Eur J Clin Pharmacol 70:1087–1095

    CAS  PubMed  Google Scholar 

  • Akamine Y, Miura M, Komori H, Tamai I, Ieiri I, Yasui-Furukori N et al (2015) The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion. Drug Metab Pharmacokinet 30:352–357

    CAS  PubMed  Google Scholar 

  • Akanuma S, Hosoya K, Ito S, Tachikawa M, Terasaki T, Ohtsuki S (2010) Involvement of multidrug resistance-associated protein 4 in efflux transport of prostaglandin E (2) across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins. J Pharmacol Exp Ther 333:912–919

    Article  CAS  PubMed  Google Scholar 

  • Akanuma S, Uchida Y, Ohtsuki S, Tachikawa M, Terasaki T, Hosoya K (2011) Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide- induced inflammation and additive inhibitory effect of cefmetazole. Fluids Barriers CNS 8:24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aleksunes LM, Cui Y, Klaassen CD (2008) Prominent expression of xenobiotic efflux transporters in mouse extraembryonic fetal membranes compared with placenta. Drug Metab Dispos 36:1960–1970

    Article  CAS  PubMed  Google Scholar 

  • Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, Lee E (2011) Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol 72:321–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amundsen R, Christensen H, Zabihyan B, Asberg A (2010) Cyclosporine A, but not tacrolimus, shows relevant inhibition of OATP1B1 mediated transport of atorvastatin. Drug Metabo Dispo 38:1499–1504

    Article  CAS  Google Scholar 

  • Andreev E, Koopman M, Arisz L (1999) A rise in plasma creatinine that is not a sign of renal failure: which drugs can be responsible? J Intern Med 246:247–252

    Article  CAS  PubMed  Google Scholar 

  • Andreev E, Brosseau N, Carmona E, Mes-Masson AM, Ramotar D (2016) The human organic cation transporter OCT1 mediates high affinity uptake of the anticancer drug daunorubicin. Sci Rep 6:20508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayyadurai S, Charania MA, Xiao B, Viennois E, Merlin D (2013) PEPT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis. Lab Investig 9:888–899

    Article  CAS  Google Scholar 

  • Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ (2002) Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685–691

    Article  CAS  PubMed  Google Scholar 

  • Backman JT, Luurila H, Neuvonen M, Neuvonen PJ (2005) Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther 78:154–167

    Article  CAS  PubMed  Google Scholar 

  • Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A et al (2012) Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 17:926–939

    Article  CAS  PubMed  Google Scholar 

  • Badagnani I, Castro RA, Taylor TR, Brett CM, Huang CC, Stryke D et al (2006) Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther 318:521–529

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Bailey DG (2010) Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 70:645–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey DG, Dresser GK, Leake BF, Kim RB (2007) Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 81:495–502

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Banerjee N, Allen C, Bendayan R (2012) Differential role of organic anion-transporting polypeptides in estrone-3-sulphate uptake by breast epithelial cells and breast cancer cells. J Pharmacol Exp Ther 342:510–519

    Article  CAS  PubMed  Google Scholar 

  • Banerjee N, Fonge H, Mikhail A, Reilly RM, Bendayan R, Allen C et al (2013) Estrone-3-sulphate, a potential novel ligand for targeting breast cancers. PLoS ONE 8:e64069

    Article  PubMed  PubMed Central  Google Scholar 

  • Banerjee N, Miller N, Allen C, Bendayan R (2014) Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues. Breast Cancer Res Treat 145:647–661

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    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, Boiselle C (2016) Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III. Xenobiotica 46:457–466

    Article  CAS  PubMed  Google Scholar 

  • Ben Hassine I, Gharbi H, Soltani I, Teber M, Farrah A, Ben Hadj Othman H et al (2017) hOCT1 gene expression predict for optimal response to Imatinib in Tunisian patients with chronic myeloid leukemia. Cancer Chemother Pharmacol 79:737–745

    Article  CAS  PubMed  Google Scholar 

  • Benet LZ (2009) The Drug transporter-metabolism alliance: uncovering and defining the interplay. Mol Pharm 6:1631–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergmann OM, Kristjansson G, Jonasson JG, Björnsson ES (2012) Jaundice due to suspected statin hepatotoxicity: a case series. Dig Dis Sci 57:1959–1964

    Article  PubMed  Google Scholar 

  • Bertoni A, Rastoldo A, Sarasso C, Di Vito C, Sampietro S, Nalin M et al (2012) Dehydroepiandrosterone-sulfate inhibits thrombin-induced platelet aggregation. Steroids 77:260–268

    Article  CAS  PubMed  Google Scholar 

  • Blache D, Becchi M, Davignon J (1995) Occurrence and biological effects of cholesteryl sulfate on blood platelets. Biochim Biophys Acta 1259:291–296

    Article  PubMed  Google Scholar 

  • Boxberger KH, Hagenbuch B, Lampe JN (2014) Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake. Drug Metab Dispos 42:990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandoni A, Torres AM (2015) Altered renal expression of relevant clinical drug transporters in different models of acute uremia in rats. Role of urea levels. Cell Physiol Biochem 36:907–916

    Article  CAS  PubMed  Google Scholar 

  • Brandsch M (2013) Drug transport via the intestinal peptide transporter PEPT1. Curr Opin Pharmacol 13:881–887

    Article  CAS  PubMed  Google Scholar 

  • Brennan BJ, Moreira SA, Morcos PN, Navarro MT, Asthappan J, Goelzer P et al (2013) Pharmacokinetics of a three-way drug interaction between danoprevir, ritonavir and the organic anion transporting polypeptide (OATP) inhibitor ciclosporin. Clin Pharmacokinet 52:805–813

    Article  CAS  PubMed  Google Scholar 

  • Brunham LR, Lansberg PJ, Zhang L, Miao F, Carter C, Hovingh GK et al (2011) Differential effect of the rs 4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J 12:233–237

    Article  CAS  PubMed  Google Scholar 

  • Bruyn TD, Fattah S, Stieger B, Augustijns P, Annaert P (2011) Sodium Fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3. J Pharm Sci 100:5018–5030

    Article  CAS  PubMed  Google Scholar 

  • Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA (2013) Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol 24:353–363

    Article  CAS  PubMed  Google Scholar 

  • Burckhardt G (2012) Drug transport by organic anion transporters (OATs). Pharmacol Ther 136:106–130

    Article  CAS  PubMed  Google Scholar 

  • Busti AJ, Bain AM, Hall RG 2nd, Bedimo RG, Leff RD, Meek C et al (2008) Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 51:605–610

    Article  CAS  PubMed  Google Scholar 

  • Buxhofer-Ausch V, Sheikh M, Ausch C, Zotter S, Bauer H, Mollik M et al (2018) Abundance of the organic anion-transporting polypeptide OATP4A1 in early-stage colorectal cancer patients: association with disease relapse. Appl Immunohistochem Mol Morphol 2018. https://doi.org/10.1097/PAI.0000000000000557

  • Buyse M, Tsocas A, Walker F, Merlin D, Bado A (2002) PEPT1-mediated fMLP transport induces intestinal inflammation in vivo. Am J Physiol Cell Physiol 283:C1795–C1800

    Article  CAS  PubMed  Google Scholar 

  • Caetano-Pinto P, Jamalpoor A, Ham J, Goumenou A, Mommersteeg M, Pijnenburg D et al (2017) Cetuximab prevents methotrexate-induced cytotoxicity in vitro through epidermal growth factor dependent regulation of renal drug transporters. Mol Pharm 14:2147–2157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao F, Gao Y, Wang M, Fang L, Ping Q (2013) Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PEPT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics. Mol Pharm 10:1378–1387

    Article  CAS  PubMed  Google Scholar 

  • Carr DF, O’Meara H, Jorgensen AL, Campbell J, Hobbs M, McCann G et al (2013) SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink. Clin Pharmacol Ther 94:695–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan T, Zhu L, Madigan MC, Wang K, Shen W, Gillies MC et al (2015) Human organic anion transporting polypeptide 1A2 (OATP1A2) mediates cellular uptake of all-trans-retinol in human retinal pigmented epithelial cells. Brit J Pharmacol 172:2343–2353

    Article  CAS  Google Scholar 

  • Chang JH, Plise E, Cheong J, Ho Q, Lin M (2013) Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Mol Pharm 10:3067–3075

    Article  CAS  PubMed  Google Scholar 

  • Charrier L, Merlin D (2006) The oligopeptide transporter hPEPT1: gateway to the innate immune response. Lab Investig 86:538–546

    Article  CAS  PubMed  Google Scholar 

  • Charrier L, Driss A, Yan Y, Nduati V, Klapproth JM, Sitaraman SV, Merlin D (2006) hPEPT1 mediates bacterial tripeptide fMLP uptake in human monocytes. Lab Investig 86:490–503

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK et al (2009a) Effect of genetic variation in the organic cation transporter 2, OCT2, on the renal elimination of metformin. Pharmacogenet Genomics 19:497–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Zhang W, Huang WH, Tan ZR, Wang YC, Huang X et al (2013) Effect of a single-dose rifampin on the pharmacokinetic pitavastatin in healthy volunteers. Eur J Clin Pharmacol 69:1933–1938

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA 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 R, Wang J, Tang S, Zhang Y, Lv X, Wu S et al (2015a) Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort. Tuberculosis (Edinb) 95:68–74

    Article  CAS  Google Scholar 

  • Chen L, Yee SW, Giacomini KM (2015b) OCT1 in hepatic steatosis and thiamine disposition. Cell Cycle 14:283–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Vapurcuyan A, Shahidullah M, Aleksunes LM, Pelis RM (2012) Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab Dispos 40:617–624

    Article  CAS  PubMed  Google Scholar 

  • Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72:23–27

    Article  CAS  PubMed  Google Scholar 

  • Cho SK, Yoon JS, Lee MG, Lee DH, Lim LA, Park K et al (2011) Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin Pharmacol Ther 89:416–421

    Article  CAS  PubMed  Google Scholar 

  • Cho AK, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Chung JY, Cho SK, Kim TH, Kim KH, Jang GH, Kim CO et al (2013) Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. Pharmacogenet Genomics 23:365–373

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstädt H 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 

  • Clarke JD, Hardwick RN, Lake AD, Canet MJ, Cherrington NJ (2014) Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression. J Pharmacol Exp Ther 348:452–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corcoran GB, Salazar DE (1989) Obesity as a risk factor in drug-induced organ injury. IV. Increased gentamicin nephrotoxicity in the obese overfed rat. J Pharmacol Exp Ther 248:17–22

    CAS  PubMed  Google Scholar 

  • Corcoran GB, Salazar DE, Schentag JJ (1988) Excessive aminoglycoside nephrotoxicity in obese patients. Am J Med 85:279

    Article  CAS  PubMed  Google Scholar 

  • Couroussé T, Gautron G (2015) Role of organic cation transporters (OCTs) in the brain. Pharmacol Ther 146:94–103

    Article  CAS  PubMed  Google Scholar 

  • Couroussé T, Bacq A, Belzung C, Guiard B, Balasse L, Louis F et al (2015) Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling. Mol Psychiatry 20:889–900

    Article  CAS  PubMed  Google Scholar 

  • Cropp CD, Komori T, Shima JE, Urban TJ, Yee SW, More SS et al (2008) Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol 73:1151–1158

    Article  CAS  PubMed  Google Scholar 

  • Csanaky IL, Lu H, Zhang Y, Ogura K, Choudhuri S, Klaassen CD (2011) Organic anion–transporting polypeptide 1b2 (Oatp 1b2) is important for the hepatic uptake of unconjugated bile acids: studies in Oatp 1b2-null mice. Hepatology 53:272–281

    Article  CAS  PubMed  Google Scholar 

  • da Cunha Vasconcelos F, Mauricio Scheiner MA, Moellman-Coelho A, Mencalha AL, Renault IZ, Rumjanek VM et al (2016) Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice. Leuk Res 51:3–10

    Article  CAS  PubMed  Google Scholar 

  • Dalmasso G, Nguyen HT, Charrier-Hisamuddin L, Yan Y, Laroui H, Demoulin B et al (2010) PEPT1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-{gamma}- D-Glu-meso-DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299:G687–G696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalmasso G, Nguyen HT, Ingersoll SA, Ayyadurai S, Laroui H, Charania MA et al (2011) The PEPT1-NOD2 signaling pathway aggravates induced colitis in mice. Gastroenterology 141:1334–1345

    Article  CAS  PubMed  Google Scholar 

  • Damman K, Perez AC, Anand IS, Komajda M, McKelvie RS, Zile MR et al (2014) Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol 64:1106–1113

    Article  CAS  PubMed  Google Scholar 

  • Damman K, Solomon SD, Pfeffer MA, Swedberg K, Yusuf S, Young JB et al (2016) Worsening renal function and outcome in heart failure patients with reduced and preserved ejection fraction and the impact of angiotensin receptor blocker treatment: data from the CHARM-study programme. Eur J Heart Fail 8:1508–1517

    Article  CAS  Google Scholar 

  • de Graan AJM, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE et al (2012) Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res 18:4433–4440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Kanter CT, Keuter M, van der Lee MJ, Koopmans PP, Burger DM (2011) Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir. Antivir Ther 16:435–437

    Article  CAS  PubMed  Google Scholar 

  • de Lima LT, Vivona D, Bueno CT, Hirata RD, Hirata MH, Luchessi AD et al (2014) Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. Med Oncol 31:851

    Article  CAS  PubMed  Google Scholar 

  • Deguchi T, Isozaki K, Yousuke K, Terasaki T, Otagiri M (2006) Involvement of organic anion transporters in the efflux of uremic toxins across the blood–brain barrier. J Neurochem 96:1051–1059

    Article  CAS  PubMed  Google Scholar 

  • Dingemanse J, van Giersbergen PL, Patat A, Nilsson PN (2010) Mutual pharmacokinetic interactions between bosentan and lopinavir/ritonavir in healthy participants. Antivir Ther 15:157–163

    Article  CAS  PubMed  Google Scholar 

  • Donovan MD, O’Brien FE, Boylan GB, Cryan JF, Griffin BT (2014) The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat. J Pharm Pharmacol 67:501–510

    Article  CAS  PubMed  Google Scholar 

  • Donovan MD, Schellekens H, Boylan GB, Cryan JF, Griffin BT (2016) In vitro bidirectional permeability studies identify pharmacokinetic limitations of NKCC1 inhibitor bumetanide. Eur J Pharmacol 770:117–125

    Article  CAS  PubMed  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, Zhou K, Donnelly LA, Tavendale R, Palmer CAN, Pearson ER (2015) Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: A GoDARTS study. Diabetes 64:1786–1793

    Article  CAS  PubMed  Google Scholar 

  • Engler JR, Frede A, Saunders VA, Zannettino AC, Hughes TP, White DL (2010) Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity. Leukemia 24:765–770

    Article  CAS  PubMed  Google Scholar 

  • Engler JR, Zannettino AC, Bailey CG, Rasko JE, Hughes TP, White DL (2011) OCT-1 function varies with cell lineage but is not influenced by BCR-ABL. Haematologica 96:213–220

    Article  PubMed  Google Scholar 

  • Enomoto A, Niwa T (2007) Roles of organic anion transporters in the progression of chronic renal failure. Ther Apher Dial 11(Suppl 1):S27–S31

    Article  CAS  PubMed  Google Scholar 

  • Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH, Anzai N et al (2002) Molecular identification of a novel carnitine transporter specific to human testis. Insights into the mechanism of carnitine recognition. J Biol Chem 277:36262–36271

    Article  CAS  PubMed  Google Scholar 

  • Eraly SA, Vallon V, Vaughn DA, Gangoiti JA, Richter K, Nagle M et al (2006) Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 281:5072–5083

    Article  CAS  PubMed  Google Scholar 

  • Erhardt S, Olsson SK, Engberg G (2009) Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 23:91–101

    Article  CAS  PubMed  Google Scholar 

  • Fan Y, Wei F, Lang Y, Wang S (2015) Losartan treatment for hypertensive patients with hyperuricaemia in Chinese population: a meta-analysis. J Hypertens 33:681–688

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fork C, Bauer T, Golz S, Geerts A, Weiland J, Del Turco D et al (2011) OAT2 catalyses efflux of glutamate and uptake of orotic acid. Biochem J 436:305–312

    Article  CAS  PubMed  Google Scholar 

  • Franke RM, Kosloske AM, Lancaster CS, Filipski KK, C H, Zolk O et al (2010) Influence of Oct 1/Oct 2-deficiency on cisplatin-induced changes in urinary N-Acetyl-β-D-glucosaminidase. Clin Cancer Res 16:4198–4206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujita D, Saito Y, Nakanishi T, Tamai I (2016) Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to gastrointestinal toxicity of anticancer drug SN-38, active metabolite of irinotecan hydrochloride. Drug Metab Dispos 44:1–7

    Article  CAS  PubMed  Google Scholar 

  • Furberg CD, Pitt B (2001) Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med 2:205–207

    Article  PubMed  PubMed Central  Google Scholar 

  • Furihata T, Matsumoto S, Fu Z, Tsubota A, Sun Y, Matsumoto S et al (2014) Different interaction profiles of directing-acting anti-hepatitis C virus agents with human organic anion transporting polypeptides. Antimicrob Agents Chemother 58:4555–4564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Futterman LG, Lemberg L (2004) Statin pleiotropy: fact or fiction? Am J Crit Care 13:244–249

    PubMed  Google Scholar 

  • Gai Z, Visentin M, Hiller C, Krajnc E, Li T, Zhen J et al (2016) Organic cation transporter 2 overexpression may confer an increased risk of gentamicin-induced nephrotoxicity. Antimicrob Agents Chemother 60:5573–5580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao B, Vavricka SR, Meier PJ, Stieger B (2015) Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS. Pflugers Arch 467:1481–1493

    Article  CAS  PubMed  Google Scholar 

  • Gasser PJ, Lowry CA, Orchinik M (2006) Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 26:8758–8766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasser PJ, Hurley MM, Chan J, Pickel VM (2017) Organic cation transporter 3 (OCT3) is localized to intracellular and surface membranes in select glial and neuronal cells within the basolateral amygdaloid complex of both rats and mice. Brain Struct Funct 222:1913–1928

    Article  CAS  PubMed  Google Scholar 

  • Geier A, Macias RIR, Bettinger D, Weiss J, Bantel H, Jahn D et al (2017) The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma. Oncotarget 8:15846–15857

    Article  PubMed  PubMed Central  Google Scholar 

  • Gilligan LC, Gondal A, Tang V, Hussain MT, Arvaniti A, Hewitt AM et al (2017) Estrone Sulfate transport and steroid sulfatase activity in colorectal cancer: implications for hormone replacement therapy. Front Pharmacol 8:103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS (2007) Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 81:363–370

    Article  CAS  Google Scholar 

  • Gong IY, Kim RB (2013) Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet 28:4–18

    Article  CAS  PubMed  Google Scholar 

  • Gong Y, Wu X, Wang T, Zhao J, Liu X, Yao Z et al (2017) Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy. Oncotarget 8:40454–40468

    PubMed  PubMed Central  Google Scholar 

  • Grimm D, Lieb J, Weyer V, Vollmar J, Darstein F, Lautem A et al (2016) Organic cation transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer 16:94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grottker J, Rosenberger A, Burckhardt G, Hagos Y (2011) Interaction of human multidrug and toxin extrusion 1 (MATE1) transporter with antineoplastic agents. Drug Metabol Drug Interact 26:181–189

    Article  CAS  PubMed  Google Scholar 

  • Grube M, Köck K, Oswald S, Draber K, Meissner K, Eckel L et al (2006) Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther 80:607–620

    Article  CAS  PubMed  Google Scholar 

  • Grube M, Reuther S, Meyer zu Schwabedissen H, Köck K, Draber K, Ritter CA et al (2007) Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. Drug Metab Dispos 35:30–35

    Article  CAS  PubMed  Google Scholar 

  • Grün B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G et al (2013) Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Brit J Clin Pharmacol 76:787–796

    Article  CAS  Google Scholar 

  • Gui C, Hagenbuch B (2009) Role of transmembrane domain 10 for the function of organic anion transporting polypeptide 1B1. Protein Sci 18:2298–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta D, Gupta SV, Dahan A, Tsume Y, Hilfinger J, Lee KD et al (2013) Increasing Oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue. Mol Pharm 10:512–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagenbuch B, Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609:1–18

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Meier PJ (2004) Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653–665

    Article  CAS  PubMed  Google Scholar 

  • Hagenbuch B, Stieger B (2013) The SLCO (former SLC21) Superfamily of transporters. Mol Asp Med 34:396–412

    Article  CAS  Google Scholar 

  • Hagiya Y, Endo Y, Yonemura Y, Takahashi K, Ishizuka M, Abe F et al (2012) Pivotal roles of peptide transporter PEPT1 and ATP-binding cassette (ABC) transporter ABCG2 in 5-aminolevulinic acid (ALA)-based photocytotoxicity of gastric cancer cells in vitro. Photodiagn Photodyn Ther 9:204–214

    Article  CAS  Google Scholar 

  • Hagiya Y, Fukuhara H, Matsumoto K, Endo Y, Nakajima M, Tanaka T et al (2013) Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer. Photodiagn Photodyn Ther 10:288–295

    Article  CAS  Google Scholar 

  • Hagos Y, Wolff NA (2010) Assessment of the role of renal organic anion transporters in drug-induced nephrotoxicity. Toxins 2:2055–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagos Y, Hundertmark P, Shnitsar V, Marada VV, Wulf G, Burckhardt G (2015) Renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake. Am J Physiol Renal Physiol 308:F330–F338

    Article  CAS  PubMed  Google Scholar 

  • Hamada T, Mizuta E, Kondo T, Hirai M, Yamada K, Kato M et al (2010) Effects of a low-dose antihypertensive diuretic in combination with losartan, telmisartan, or candesartan on serum urate levels in hypertensive patients. Arzneimittelforschung 60:71–75

    CAS  PubMed  Google Scholar 

  • Hamre K, Tharp R, Poon K, Xiong X, Smeyne RJ (1999) Differential strain susceptibility following 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus. Brain Res 828:91–103

    Article  CAS  PubMed  Google Scholar 

  • Han YH, Busler D, Hong Y, Tian Y, Chen C, Rodrigues AD (2010) Transporter studies with the 3-O-sulfate conjugate of 17alpha-ethinylestradiol: assessment of human liver drug transporters. Drug Metab Dispos 38:1072–1082

    Article  CAS  PubMed  Google Scholar 

  • Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D et al (2010) HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics 20:112–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto Y, Tatsumi S, Takeda R, Naka A, Ogane N et al (2014) Expression of organic anion-transporting polypeptide 1A2 and organic cation transporter 6 as a predictor of pathologic response to neoadjuvant chemotherapy in triple negative breast cancer. Breast Cancer Res Treat 145:101–111

    Article  CAS  PubMed  Google Scholar 

  • Hays A, Apte U, Hagenbuch B (2013) Organic anion transporting polypeptides expressed in pancreatic cancer may serve as potential diagnostic markers and therapeutic targets for early stage adenocarcinomas. Pharm Res 30:2260–2269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He R, Zhang D, Lu W, Zheng T, Wan L, Liu F et al (2015) SLC47A1 gene rs 2289669 G > A variants enhance the glucose-lowering effect of metformin via delaying its excretion in Chinese type 2 diabetes patients. Diabetes Res Clin Pract 109:57–63

    Article  CAS  PubMed  Google Scholar 

  • Heise M, Lautem A, Knapstein J, Schattenberg JM, Hoppe-Lotichius M, Foltys D et al (2012) Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer 12:109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henjakovic M, Hagos Y, Krick W, Burckhardt G, Burckhardt BC (2015) Human organic anion transporter 2 is distinct from organic anion transporters 1 and 3 with respect to transport function. Am J Physiol Renal Physiol 309:F843–F851

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hill JE, Gasser PJ (2013) Organic cation transporter 3 is densely expressed in the intercalated cell groups of the amygdala: anatomical evidence for a stress hormone-sensitive dopamine clearance system. J Chem Neuroanat 52:36–43

    Article  CAS  PubMed  Google Scholar 

  • Hirano M, Maeda K, Shitara Y, Sugiyama Y (2004) Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 311:139–146

    Article  CAS  PubMed  Google Scholar 

  • Ho ES, Lin DC, Mendel DB, Cihlar T (2000) Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol 11:383–393

    CAS  PubMed  Google Scholar 

  • Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG et al (2007) Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics 17:647–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC et al (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci 33:10534–10543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosoya K, Tachikawa M (2011) Roles of organic anion/cation transporters at the blood–brain and blood–cerebrospinal fluid barriers involving uremic toxins. Clin Exp Nephrol 15:478–485

    Article  CAS  PubMed  Google Scholar 

  • Hosoya K, Makihara A, Tsujikawa Y, Yoneyama D, Mori S, Terasaki T et al (2009) Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercaptopurine. J Pharmacol Exp Ther 329:87–93

    Article  CAS  PubMed  Google Scholar 

  • Hou Q, Li S, Li L, Li Y, Sun X, Tian H (2015a) Association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk. A meta-analysis of case–control studies. Medicine e1268:94

    Google Scholar 

  • Hou W, Zhang D, Lu W, Zheng T, Wan L, Li Q et al (2015b) Polymorphism of organic cation transporter 2 improves glucose-lowering effect of metformin via influencing its pharmacokinetics in Chinese type 2 diabetic patients. Mol Diagn Ther 19:25–33

    Article  CAS  PubMed  Google Scholar 

  • Hsueh CH, Yoshida K, Zhao P, Meyer TW, Zhang L et al (2016) Identification and quantitative assessment of uremic solutes as inhibitors of renal organic anion transporters, OAT1 and OAT3. Mol Pharm 13:3130–3140

    Article  CAS  PubMed  Google Scholar 

  • Hu ZY (2013) Disposition pathway-dependent approach for predicting organic anion-transporting polypeptide-mediated drug-drug interactions. Clin Pharmacokinet 52:433–441

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Smith DE (2016) Species differences in the pharmacokinetics of cefadroxil as determined in wild type and humanized PEPT1 mice. Biochem Pharmacol 107:81–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Shen H, Keep RF, Smith DE (2007) Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity. J Neurochem 103:2058–2065

    Article  CAS  PubMed  Google Scholar 

  • Hu Y, Smith DE, Ma K, Jappar D, Thomas W, Hillgren KM (2008) Targeted disruption of peptide transporter PEPT1 Gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 5:1122–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A (2014a) Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer 110:894–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Xie Y, Keep RF, Smith DE (2014b) Divergent developmental expression and function of the proton-coupled oligopeptide transporters PEPT2 and PHT1 in regional brain slices of mouse and rat. J Neurochem 129:955–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Li N, Hong W, Zhan K, Yu X, Huang H et al (2013) Conserved tryptophan residues within putative transmembrane domain 6 affect transport function of organic anion transporting polypeptide 1B1. Mol Pharmacol 84:521–527

    Article  CAS  PubMed  Google Scholar 

  • Hubeny A, Keiser M, Oswald S, Jedlitschky G, Kroemer HK, Siegmund W et al (2016) Expression of organic anion transporting polypeptide 1A2 in red blood cells and its potential impact on antimalarial therapy. Drug Metab Dispos 44:1562–1568

    Article  CAS  PubMed  Google Scholar 

  • Huber RD, Gao B, Sidler Pfändler MA, Zhang-Fu W, Leuthold S, Hagenbuch B et al (2007) Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain. Am J Physiol Cell Physiol 292:C795–C806

    Article  CAS  PubMed  Google Scholar 

  • Hucke A, Ciarimboli G (2016) The Role of Transporters in the toxicity of chemotherapeutic drugs: focus on transporters for organic cations. J Clin Pharmacol 56(Suppl 7):S157–S172

    Article  CAS  PubMed  Google Scholar 

  • Hussner J, Begunk R, Boettcher K, Gliesche DG, Prestin KP, Meyer zu Schwabedissen HE et al (2015) Expression of OATP2B1 as determinant of drug effects in the microcompartment of the coronary artery. Vasc Pharmacol 72:25–34

    Article  CAS  Google Scholar 

  • Imamura Y, Murayama N, Okudaira N, Kurihara A, Okazaki O, Izumi T et al (2011) Prediction of fluoroquinolone-induced 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 

  • Imamura Y, Tsuruya Y, Damme K, Heer D, Kumagai Y, Maeda K et al (2014) 6β-Hydroxycortisol is an endogenous probe for evaluation of drug-drug interactions involving a multispecific renal organic anion transporter, OAT3/SLC22A8, in healthy subjects. Drug Metab Dispos 42:685–694

    Article  CAS  PubMed  Google Scholar 

  • Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D (2012) The role and pathophysiological relevance of membrane transporter Pep T1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302:G484–G492

    Article  CAS  PubMed  Google Scholar 

  • Ingraham L, Li M, Renfro JL, Parker S, Vapurcuyan A, Hanna I et al (2014) A plasma concentration of α-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1. Mol Pharmacol 86:86–95

    Article  CAS  PubMed  Google Scholar 

  • Ishiguro N, Maeda K, Kishimoto W, Saito A, Harada A, Ebner T et al (2006) Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos 34:1109–1115

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ito S, Kusuhara H, Kumagai Y, Moriyama Y, Inoue K, Kondo T et al (2012a) N-methylnicotinamide is an endogenous probe for evaluation of drug-drug interactions involving multidrug and toxin extrusions (MATE1 and MATE2-K). Clin Pharmacol Ther 92:635–641

    Article  CAS  PubMed  Google Scholar 

  • Ito S, Kusuhara H, Yokochi M, J Toyoshima J, Inoue K, Yuasa H et al (2012b) 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 

  • Iusuf D, Hendrikx JJMA, van Esch A, van de Steeg E, Els Wagenaar E, Rosing H et al (2015) Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer 136:225–233

    Article  CAS  PubMed  Google Scholar 

  • Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I (2007) Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. J Pharmacol Exp Ther 320:211–217

    Article  CAS  PubMed  Google Scholar 

  • Iwata K, Aizawa K, Kamitsu S, Jingami S, Fukunaga E, Yoshida M et al (2012) 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 6:843–851

    Article  CAS  Google Scholar 

  • Izumi S, Nozaki Y, Komori T, Maeda K, Takenaka Q, Kusano K et al (2013) Substrate-dependent inhibition of organic anion transporting polypeptide 1B1: comparative analysis with prototypical probe substrates estradiol-17β-glucuronide, estrone-3-sulfate, and sulfobromophthaleins. Drug Metab Dispos 41:1859–1866

    Article  CAS  PubMed  Google Scholar 

  • Izumi S, Nozaki Y, Maeda K, Komori T, Takenaka O, Kusuhara H et al (2015) Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1b1 inhibition profiles for the prediction of drug-drug interactions. Drug Metab Dispos 43:235–247

    Article  CAS  PubMed  Google Scholar 

  • Jacobson TA (2004) Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P 450 inhibitors. Am J Cardiol 94:1140–1146

    Article  CAS  PubMed  Google Scholar 

  • Jappar D, Wu SP, Hu Y, Smith DE (2010) Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and pept 1 knockout mice. Drug Metab Dispos 38:1740–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y (2002) Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug Metabol Drug Interact 19:41–48

    Article  CAS  PubMed  Google Scholar 

  • Jeon H, Jang IJ, Lee SH, Ohashi K, Kotegawa T, Ieiri I et al (2012) Apple juice greatly reduces systemic exposure to atenolol. Br J Clin Pharmacol 75:172–179

    Article  CAS  PubMed Central  Google Scholar 

  • Jin HE, Hong SS, Choi MK, Maeng HJ, Kim DD, Chung SJ et al (2009) Reduced antidiabetic effect of metformin and down-regulation of hepatic Oct 1 in rats with ethynylestradiol-induced cholestasis. Pharm Res 26:549–559

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jung KY, Takeda M, Shimoda M, Narikawa S, Tojo A, Kim DK et al (2002) Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1. Life Sci 70:1861–1874

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kagawa T, Oka A, Kobayashi Y, Hiasa Y, Kitamura T, Sakugawa H et al (2015) Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype. Hum Mutat 36:327–232

    Article  CAS  PubMed  Google Scholar 

  • Kajiwara M, Terada T, Ogasawara K, Iwano J, Katsura T, Fukatsu A et al (2009) Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. Hum Genet 54:40–66

    Article  CAS  Google Scholar 

  • Kajiwara M, Ban T, Matsubara K, Nakanishi Y, Masuda S (2016) Urinary dopamine as a potential index of the transport activity of multidrug and toxin extrusion in the kidney. Int J Mol Sci 17:1228

    Article  CAS  PubMed Central  Google Scholar 

  • Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Brit J Pharmacol 158:693–705

    Article  CAS  Google Scholar 

  • Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M (2008) Different effects of SLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J Clin Pharmacol 48:311–321

    Article  CAS  PubMed  Google Scholar 

  • Kamal MA, Keep RF, Smith DE (2008) Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharmacokinet 23:236–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamal MA, Jiang H, Hu Y, Keep RF, Smith DE (2009) Influence of genetic knockout of PEPT2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and PEPT2 null mice. Am J Physiol Regul Integr Comp Physiol 296:R986–R991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y et al (2012) Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug−drug interactions. J Med Chem 55:4740–4763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato K, Shirasaka Y, Kuraoka E, Kikuchi A, Iguchi M, Suzuki H et al (2010) Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. Mol Pharm 7:1747–1756

    Article  CAS  PubMed  Google Scholar 

  • Kato K, Mori H, Kito YM, Ito S, Inoue K et al (2014) Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins. Pharm Res 31:136–147

    Article  CAS  PubMed  Google Scholar 

  • Keppler D (2014) The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 42:561–565

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kikuchi T, Okamura T, Wakizaka H, Okada M, Odaka K, Yui J et al (2014) OAT3-mediated extrusion of the 99mTc-ECD metabolite in the mouse brain. J Cereb Blood Flow Metab 34:585–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimoto E, Yoshida K, Balogh LM, Bi YA, Maeda K, El-Kattan A et al (2012) Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol Pharm 9:3535–3542

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kindla J, Müller F, Mieth M, Fromm MF, König J (2011) Influence of non-steroidal anti- inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos 39:1047–1053

    Article  CAS  PubMed  Google Scholar 

  • Kinoshita J, Iwata N, Kimotsuki T, Yasuda M (2014) Digoxin-induced reversible dysfunction of the cone photoreceptors in monkeys. Invest Ophthalmol Vis Sci 55:881–892

    Article  CAS  PubMed  Google Scholar 

  • Kis O, Zastre JA, Ramaswamy M, Bendayan R (2010) pH dependence of organic anion-transporting polypeptide 2B1 in Caco-2 cells: potential role in antiretroviral drug oral bioavailability and drug–drug interactions. J Pharmacol Exp Ther 334:1009–1022

    Article  CAS  PubMed  Google Scholar 

  • Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW (2008) Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 47:570–578

    Article  CAS  PubMed  Google Scholar 

  • Klein K, Jüngst C, Mwinyi J, Stieger B, Krempler F, Patsch W et al (2010) The human organic anion transporter genes OAT5 and OAT7 are transactivated by hepatocyte nuclear factor-1α (HNF-1α). Mol Pharmacol 78:1079–1087

    Article  CAS  PubMed  Google Scholar 

  • Klen J, Goričar K, Janež A, Dolžan V (2014) 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 2014:934729

    Article  PubMed  PubMed Central  Google Scholar 

  • Knütter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K et al (2008) Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther 327:432–441

    Article  CAS  PubMed  Google Scholar 

  • Knütter I, Kottra G, Fischer W, Daniel H, Brandsch M (2009) High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos 37:143–149

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama YT (2005) Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharmacol 57:573–578

    Article  CAS  PubMed  Google Scholar 

  • Koepsell H (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Asp Med 34:413–435

    Article  CAS  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 

  • König J, Seithel A, Gradhand U, Fromm MF (2006) Pharmacogenomics of human OATP transporters. Naunyn Schmiedeberg’s Arch Pharmacol 372:432–443

    Article  CAS  Google Scholar 

  • König J, Zolk O, Singer K, Hoffmann C, Fromm MF (2011) Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations. Brit J Pharmacol 163:546–555

    Article  CAS  Google Scholar 

  • Koren-Michowitz M, Buzaglo Z, Ribakovsky E, Schwarz M, Pessach I, Shimoni A et al (2014) OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients. Eur J Haematol 92:283–288

    Article  CAS  PubMed  Google Scholar 

  • Kotsampasakou E, Brenner S, Jäger W, Ecker GF (2015) Identification of novel inhibitors of organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) using a consensus vote of six classification models. Mol Pharm 12:4395–4404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozak R, Campbell BM, Strick CA, Horner W, Hoffmann WE, Kiss T et al (2014) Reduction of brain kynurenic acid improves cognitive function. J Neurosci 34:10592–10602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kudo M, Katayoshi T, Kobayashi-Nakamura K, Akagawa M, Tsuji-Naito K (2016) H+/peptide transporter (PEPT2) is expressed in human epidermal keratinocytes and is involved in skin oligopeptide transport. Biochem Biophys Res Commun 475:335–341

    Article  CAS  PubMed  Google Scholar 

  • Kullak-Ublick GA, . Ismair MG, Stieger B, Landmann L, Huber R, . Pizzagalli F et al (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525-533

    Article  CAS  PubMed  Google Scholar 

  • Kunii E, Oguri T, Kasai D, Ozasa H, Uemura T, Takakuwa O et al (2015) Organic cation transporter OCT6 mediates cisplatin uptake and resistance to cisplatin in lung cancer. Cancer Chemother Pharmacol 75:985–991

    Article  CAS  PubMed  Google Scholar 

  • Kunze A, Huwyler J, Camenisch G, Poller B (2014) Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos 42:1514–1521

    Article  CAS  PubMed  Google Scholar 

  • Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y et al (2011) Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 89:837–844

    Article  CAS  PubMed  Google Scholar 

  • Lacy SA, Hitchcock MJ, Lee WA, Tellier P, Cundy KC (1998) Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 44:97–106

    Article  CAS  PubMed  Google Scholar 

  • Lau YY, Huang Y, Frassetto L, Benet LZ (2007) Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther 81:194–204

    Article  CAS  PubMed  Google Scholar 

  • Lautem A, Heise M, Gräsel A, Hoppe-Lotichius M, Weiler N, Foltys D et al (2013) Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma. Int J Oncol 42:1297–1304

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lee A, Cooper MG, Craig JC, Knight JF, Keneally JP (1999) The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on postoperative renal function: a meta-analysis. Anaesth Intensive Care 27:574–580

    Article  CAS  PubMed  Google Scholar 

  • Lee W, Glaeser H, Smith LH, Roberts RL, Moeckel GW, Gervasini G et al (2005) Polymorphisms in human organic anion transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 280:9610–9617

    Article  CAS  PubMed  Google Scholar 

  • Lee HH, Leake BF, Teft W, Tirona RG, . Kim RB, Ho RH (2015) Contribution of hepatic organic anion transporting polypeptides (OATPs) to docetaxel uptake and clearance. Mol Cancer Ther 14: 994-1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lepist EI, Zhang X, Hao J, Huang J, osaka A, irkus G 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 

  • Leuthold S, Hagenbuch B, Mohebbi N, Wagner CA, Meier PJ, Stieger B (2009) Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters. Am J Physiol Cell Physiol 296:C570–C582

    Article  CAS  PubMed  Google Scholar 

  • Li L, Lee TK, Meier PJ, Ballatori N (1998) Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp 1, the hepatic sinusoidal organic solute transporter. J Biol Chem 273:16184–16191

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Liu F, Zheng TS, Tang JL, Lu HJ, Jia WP (2010) SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin. Acta Pharmacol Sin 31:184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Chen Y, Zhang S, More SS, Huang X, Giacomini KM (2011) Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine (pyridine) chloroplatinum (II) and oxaliplatin in mice. Pharm Res 28:610–625

    Article  CAS  PubMed  Google Scholar 

  • Li LM, Chen L, Deng GH, Tan WT, Dan YJ, Wang RQ (2012) SLCO1B1∗15 haplotype is associated with rifampin-induced liver injury. Mol Med Rep 6:75–82

    PubMed  Google Scholar 

  • Li L, Agarwal S, Elmquist WF (2013a) Brain efflux index to investigate the influence of active efflux on brain distribution of pemetrexed and methotrexate. Drug Metab Dispos 41:659–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Guo D, Dong Z, Zhang W, Zhang L, Huang SM et al (2013b) Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol 273:100–109

    Article  CAS  PubMed  Google Scholar 

  • Li L, Tu M, Yang X, Sun S, Wu X, Zhou H et al (2014) The contribution of human OCT1, OCT3, and CYP3A4 to nitidine chloride-induced hepatocellular toxicity. Drug Metab Dispos 42:1227–1234

    Article  CAS  PubMed  Google Scholar 

  • Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ (2008) Tissue distribution, ontogeny and induction of the transporters Multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci 83:59–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ (2003) Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther 73:192–198

    Article  CAS  PubMed  Google Scholar 

  • Lilja JJ, Juntti-Patinen L, Neuvonen PJ (2004) Orange juice substantially reduces the bioavailability of the β-adrenergic–blocking agent celiprolol. Clin Pharmacolo Ther 75:184–190

    Article  CAS  Google Scholar 

  • Lilja JJ, Raaska K, Neuvonen PJ (2005) Effects of orange juice on the pharmacokinetics of atenolol. Eur J Clin Pharmacol 61:337–340

    Article  CAS  PubMed  Google Scholar 

  • Lim CK, Fernández-Gomez FJ, Braidy N, Estrada C, Costa C, Costa S et al (2017) Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Prog Neurobiol 155:76–95

    Article  CAS  PubMed  Google Scholar 

  • Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY et al (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

    Article  CAS  PubMed  Google Scholar 

  • Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G et al (2012) Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull 38:426–432

    Article  PubMed  Google Scholar 

  • Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F et al (2008) SLCO1B1 variants and statin-induced myopathy -a genomewide study. N Engl J Med 359:789–799

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Liu R, Tang AM, Tan YL, Limenta LM, Lee EJ (2011) Effects of sodium bicarbonate and ammonium chloride pre-treatments on PEPT2 (SLC15A2) mediated renal clearance of cephalexin in healthy subjects. Drug Metab Pharmacokinet 26:87–93

    Article  PubMed  Google Scholar 

  • Liu HC, Jamshidi N, Chen Y, Eraly SA, Cho SY, Bhatnagar V et al (2016) An organic anion transporter 1 (OAT1)-centered metabolic network. J Biol Chem 291:19474–19486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu JE, Liu XY, Chen S, Zhang Y, Cai LY, Yang M et al (2017) SLCO1B1 521T>C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study. Eur J Clin Pharmacol 73:1409–1416

    Article  CAS  PubMed  Google Scholar 

  • Lopez JL, Tayek JA (2016) Voriconazole-induced hepatitis via simvastatin- and lansoprazole-mediated drug interactions: A case report and review of the literature. Drug Metab Dispos 44:124–126

    Article  CAS  PubMed  Google Scholar 

  • Losordo DW, Isner JM, Diaz-Sandoval LJ (2003) Endothelial recovery: the next target in restenosis prevention. Circulation 107:2635–2637

    Article  PubMed  Google Scholar 

  • Lozano E, Herraez E, Briz O, Robledo VS, Hernandez-Iglesias J, Gonzalez-Hernandez A et al (2013) Role of the plasma membrane transporter of organic cations oct 1 and its genetic variants in modern liver pharmacology. Biomed Res Int 2013:692071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X, Chan T, Xu C, Zhu L, Zhou QT, Roberts KD et al (2016) Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins. J Antimicrob Chemother 71:403–412

    Article  CAS  PubMed  Google Scholar 

  • Maeda K (2015) Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs. Biol Pharm Bull 38:155–168

    Article  CAS  PubMed  Google Scholar 

  • Maeda K, Ieiri I, Yasuda K, Fujino A, Fujiwara H, Otsubo K et al (2006) Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79:427–439

    Article  CAS  PubMed  Google Scholar 

  • Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y et al (2011) Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther 90:575–581

    Article  CAS  PubMed  Google Scholar 

  • Maeda K, Tian Y, Fujita T, Ikeda Y, Kumagai Y, Kondo T et al (2014) Inhibitory effects of p-aminohippurate and probenecid on the renal clearance of adefovir and benzylpenicillin as probe drugs for organic anion transporter (OAT) 1 and OAT3 in humans. Eur J Pharm Sci 59:94–103

    Article  CAS  PubMed  Google Scholar 

  • Mahagita C, Grassl SM, Piyachaturawat P, Ballatori N (2007) Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport. Am J Physiol Gastrointest Liver Physiol 293:G271–G278

    Article  CAS  PubMed  Google Scholar 

  • Marada VV, Flörl S, Kühne A, Müller J, Burckhardt G, Hagos Y (2015) Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) with antineoplastic drugs. Pharmacol Res 91:78–87

    Article  CAS  PubMed  Google Scholar 

  • Martina V, Benso A, Gigliardi VR, Masha A, Origlia C, Granata R et al (2006) Short-term dehydroepiandrosterone treatment increases platelet cGMP production in elderly male subjects. Clin Endocrinol 64:260–264

    Article  CAS  Google Scholar 

  • Martinez-Becerra P, Briz O, Romero MR, Macias RI, Perez MJ, Sancho-Mateo C et al (2011) Further characterization of the electrogenicity and pH sensitivity of the human organic anion-transporting polypeptides OATP1B1 and OATP1B3. Mol Pharmacol 79:596–607

    Article  CAS  PubMed  Google Scholar 

  • Masereeuw R, Mutsaers HA, Toyohara T, Abe T, Jhawar S, Sweet DH et al (2014) The kidney and uremic toxin removal: glomerulus or tubule? Semin Nephrol 34:191–208

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto J, Ariyoshi N, Sakakibara M, Nakanishi T, Okubo Y, Shiina N et al (2015) Organic anion transporting polypeptide 2B1 expression correlates with uptake of estrone-3-sulfate and cell proliferation in estrogen receptor-positive breast cancer cells. Drug Metabo Pharmacokinet 30:133–141

    Article  CAS  Google Scholar 

  • Matsumura K, Arima H, Tominaga M, Ohtsubo T, Sasaguri T, Fujii K et al (2015) Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study. Clin Exp Hypertens 37:192–196

    Article  CAS  PubMed  Google Scholar 

  • Mayerl S, Müller J, Bauer R, Richert S, Kassmann CM, Darras VM et al (2014) Transporters MCT8 and OATP1C1maintain murine brain thyroid hormone homeostasis. J Clin Invest 124:1987–1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A et al (2012) Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the atherosclerosis risk in Communities cohort study. Arthritis Rheum 64:121–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meier-Abt F, Mokrab Y, Mizuguchi K (2005) Organic anion transporting polypeptides of the oatp/slco superfamily: identification of new members in nonmammalian species, comparative modeling and a potential transport mode. J Membrane Biol 208:213–227

    Article  CAS  Google Scholar 

  • Merlin D, Si-Tahar M, Sitaraman SV, Eastburn K, Williams I, Liu X et al (2001) Colonic epithelial hPEPT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1molecules. Gastroenterology 120:1666–1679

    Article  CAS  PubMed  Google Scholar 

  • Meyer Zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB (2008) Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 68:9338–9347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer zu Schwabedissen HE, Ware JA, Finkelstein D, Chaudhry AS, Lemay S, Leon-Ponte M et al (2011) Hepatic OATP transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis. Hepatology 54:644–654

    Article  CAS  PubMed  Google Scholar 

  • Meyer zu Schwabedissen HE, Boettcher K, Steiner T, Schwarz UI, Keiser M, Kroemer HK et al (2014) OATP1B3 is expressed in pancreatic β-islet cells and enhances the insulinotropic effect of the sulfonylurea derivative glibenclamide. Diabetes 63:775–784

    Article  CAS  PubMed  Google Scholar 

  • Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T et al (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66:535–542

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misaka S, Yatabe J, Muller F, Takano K, Kawabe K, Glaeser H et al (2014) Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther 95:432–438

    Article  CAS  PubMed  Google Scholar 

  • Mitsuoka K, Miyoshi S, Kato Y, Murakami Y, Utsumi R, Kubo Y et al (2008) Cancer detection using a PET tracer, 11C-glycylsarcosine, targeted to H+/peptide transporter. J Nucl Med 49:615–622

    Article  CAS  PubMed  Google Scholar 

  • Miyajima M, Kusuhara H, Fujishima M, Adachi Y, i Sugiyama Y (2011) Organic anion transporter 3 mediates the efflux transport of an amphipathic organic anion, dehydroepiandrosterone sulfate, across the blood-brain barrier in mice. Drug Metab Dispos 39:814–819

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Moreno A, Fortún J, Graus J, Rodriguez-Gandía MA, Quereda C, Pérez-Elías MJ et al (2011) Severe rhabdomyolysis due to rosuvastatin in a liver transplant subject with human immunodeficiency virus and immunosuppressive therapy-related dyslipidemia. Liver Transpl 17:331–333

    Article  PubMed  Google Scholar 

  • Motohashi H, Inui K (2013) Organic Cation Transporter OCT (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 15:581–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mück W, Ochmann K, Rohde G, Unger S, Kuhlmann J (1998) Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol 53:469–473

    Article  PubMed  Google Scholar 

  • Mück W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S et al (1999) Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 65:251–261

    Article  PubMed  Google Scholar 

  • Mulato AS, Ho ES, Cihlar T (2000) Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther 295:10–15

    CAS  PubMed  Google Scholar 

  • Mulgaonkar A, Venitz J, Gründemann D, Sweet DH (2013) Human organic cation transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as disposition pathways for fluoroquinolone antimicrobials. Antimicrob Agents Chemother 57:2705–2711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Müller F, König J, Hoier E, Mandery K, Fromm MF (2013) Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol 86:808–815

    Article  CAS  PubMed  Google Scholar 

  • Müller F, Pontones CA, Renner BR, Mieth M, Hoier E et al (2015) N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction. Eur J Clin Pharmacol 71:85–94

    Article  CAS  PubMed  Google Scholar 

  • Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T (2004) Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 75:415–421

    Article  CAS  PubMed  Google Scholar 

  • Nagle MA, Wu W, Eraly SA, Nigam SK (2013) Organic anion transport pathways in antiviral handling in choroid plexus in Oat 1 (Slc 22a6) and Oat 3 (Slc 22a8) deficient tissue. Neurosci Lett 534:133–138

    Article  CAS  PubMed  Google Scholar 

  • Nakakariya M, Shimada T, Irokawa M, Maeda T, Tamai I (2008) Identification and species similarity of OATP transporters responsible for hepatic uptake of β-lactam antibiotics. Drug Metab Pharmacokinet 23:347–355

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui KI (2010) Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharamcol 80:762–1767

    Article  CAS  Google Scholar 

  • Nakanishi T, Tamai I (2017) Roles of Organic Anion Transporting Polypeptide 2A1 (OATP2A1/SLCO2A1) in Regulating the Pathophysiological Actions of Prostaglandins. AAPS J 20:13

    Article  CAS  PubMed  Google Scholar 

  • Nässl AM, Rubio-Aliaga I, Fenselau H, Marth MK, Kottra G, Daniel H (2011) Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 301:G128–G137

    Article  CAS  PubMed  Google Scholar 

  • Nguyen HT, Dalmasso G, Powell KR, Yan Y, Bhatt S, Kalman D et al (2009) Pathogenic bacteria induce colonic Pep T1 expression: an implication in host defense response. Gastroenterology 137:1435–1447

    Article  CAS  PubMed  Google Scholar 

  • Niemi M, Pasanen MK, Neuvonen PJ (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63:157–181

    Article  CAS  PubMed  Google Scholar 

  • Nies AT, Schwab M, Keppler D (2008) Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol 4:545–568

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Nies AT, Damme K, Kruck S, Schaeffeler E, Schwab M (2016) Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch Toxicol 90:1555–1584

    Article  CAS  PubMed  Google Scholar 

  • Nieskens TT, Peters JG, Schreurs MJ, Smits N, Woestenenk R, Jansen K et al (2016) A human renal proximal tubule cell line with stable organic anion transporter 1 and 3 expression predictive for antiviral-induced toxicity. AAPS J 18:465–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niessen J, Jedlitschky G, Grube M, Bien S, Schwertz H, Ohtsuki S et al (2009) Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin. Drug Metabo Dispo 37:1129–1137

    Article  CAS  Google Scholar 

  • Nieuweboer AJM, Hu S, Hagenbuch B, Moghaddam-Helmantel JG, Gibson AA, de Bruijn P et al (2014) Influence of drug formulation on OATP1B-mediated transport of paclitaxel. Cancer Res 74:3137–3145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nigam SK, Wu W, Bush KT, Hoenig MP, Blantz RC, Bhatnagar V (2015) Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin J Am Soc Nephrol 10:2039–2049

    Google Scholar 

  • Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindströ MLH et al (2005) Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80:315–322

    Article  CAS  PubMed  Google Scholar 

  • Nishino S, Itoh A, Matsuoka H, Maeda K, Kamoshida S (2013) Immunohistochemical analysis of organic anion transporter 2 and reduced folate carrier 1 in colorectal cancer: significance as a predictor of response to oral uracil/ftorafur plus leucovorin chemotherapy. Mol Clin Oncol 1:661–667

    PubMed  PubMed Central  Google Scholar 

  • Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T et al (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565

    Article  CAS  PubMed  Google Scholar 

  • Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, Renner EL, Clavien PA (2007) Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology 133:608–618

    Article  CAS  PubMed  Google Scholar 

  • Noé J, Portmann R, Brun ME, Funk C (2007) Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos 35:1308–1314

    Article  CAS  PubMed  Google Scholar 

  • Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I (2004) Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther 308:438–445

    Article  CAS  PubMed  Google Scholar 

  • Obach RS, Lombardo F, Waters NJ (2008) Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dispos 36:1385–1405

    Article  CAS  PubMed  Google Scholar 

  • Obaidat A, Roth M, Hagenbuch B (2012) The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol 52:135–151

    Article  CAS  PubMed  Google Scholar 

  • Ocheltree SM, Shen H, Hu Y, Keep RF, Smith DE (2005) Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: in vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J Pharmacol Exp Ther 315:240–247

    Article  CAS  PubMed  Google Scholar 

  • Oguri T, Kunii E, Fukuda S, Sone K, Uemura T, Takakuwa O et al (2016) Organic cation transporter 6 directly confers resistance to anticancer platinum drugs. Biomed Rep 5:639–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ohta KY, Imamura Y, Okudaira N, Atsumi R, Inoue K, Yuasa H (2009) Functional characterization of multidrug and toxin extrusion protein 1 as a facilitative transporter for fluoroquinolones. J Pharmacol Exp Ther 328:628–634

    Article  CAS  PubMed  Google Scholar 

  • Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M (2002) Role of blood–brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem 83:57–66

    Article  CAS  PubMed  Google Scholar 

  • Ohya H, Shibayama Y, Ogura J, Narumi K, Kobayashi M, Iseki K (2015) Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull 38:582–586

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pak YA, Long AJ, Annes WF, Witcher JW, Knadler MP, Ayan-Oshodi MA et al (2017) In vitro and clinical evaluations of the drug-drug interaction potential of a metabotropic glutamate 2/3 receptor agonist prodrug with intestinal peptide transporter 1. Drug Metab Dispos 45:137–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasanen MK, Backman JT, Neuvonen PJ, Niemi M (2006a) Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population. Eur J Clin Pharmacol 62:409–415

    Article  CAS  PubMed  Google Scholar 

  • Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006b) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16:873–879

    Article  CAS  PubMed  Google Scholar 

  • Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82:726–733

    Article  CAS  PubMed  Google Scholar 

  • Pasanen MK, Neuvonen PJ, Niemi M (2008) Global analysis of genetic variation in SLCO1B1. Pharmacogenomics 9:19–33

    Article  CAS  PubMed  Google Scholar 

  • Pathan E, Gaitonde S, Rajadhyaksha S, Sule A, Mittal G, Joshi VR (2003) A longitudinal study of serum creatinine levels in patients of rheumatoid arthritis on long term NSAID therapy. J Assoc Physicians India 51:1045–1049

    CAS  PubMed  Google Scholar 

  • Pfennig T, Herrmann B, Bauer T, Schömig E, Gründemann D (2013) Benzoic acid and specific 2-oxo acids activate hepatic efflux of glutamate at OAT2. Biochim Biophys Acta 1828:491–498

    Article  CAS  PubMed  Google Scholar 

  • Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P et al (2017) Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 43(Suppl 1):S211

    Article  PubMed Central  Google Scholar 

  • Posada MM, Smith DE (2013a) Relevance of Pep T1 in the intestinal permeability and oral absorption of cefadroxil. Pharm Res 30:1017–1025

    Article  CAS  PubMed  Google Scholar 

  • Posada MM, Smith DE (2013b) In vivo absorption and disposition of cefadroxil after escalating oral doses in wild-type and Pep T1 knockout mice. Pharm Res 30:2931–2939

    Article  CAS  PubMed  Google Scholar 

  • Prado Y, Saavedra N, Zambrano T, Lagos J, Rosales A, Salazar LA (2015) SLCO1B1 c.388A>G polymorphism is associated with HDL-C levels in response to atorvastatin in Chilean individuals. Int J Mol Sci 16:20609–20619

    Google Scholar 

  • Qian CY, Zheng Y, Wang Y, Chen J, Liu JY, Zhou HH et al (2016) Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients. Chin J Cancer 35:85

    Article  PubMed  PubMed Central  Google Scholar 

  • Rawłuszko-Wieczorek AA, Horst N, Horbacka K, Bandura AS, Świderska M, Krokowicz P et al (2015) Effect of DNA methylation profile on OATP3A1 and OATP4A1 transcript levels in colorectal cancer. Biomed Pharmacother 74:233–242

    Article  CAS  PubMed  Google Scholar 

  • Regazzi MB, Campana IC, Raddato V, Lesi C, Perani G, Gavazzi A et al (1993) Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients. Transplant Proc 25:2732–2734

    CAS  PubMed  Google Scholar 

  • Rizwan AN, Burckhardt G (2007) Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm Res 24:450–470

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues AC, Perin PMS, Purim RG, Silbiger VN, Genvigir FDV, Willrich MAV et al (2011) Pharmacogenetics of OATP transporters reveals that SLCO1B1 c.388A>G variant is determinant of increased atorvastatin response. Int J Mol Sci 12:5815–5827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Römermann K, Fedrowitz M, Hampel P, Kaczmarek E, Töllner K, Erker T et al (2017) Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain. Neuropharmacology 117:182–194

    Article  CAS  PubMed  Google Scholar 

  • Roth M, Timmermann BN, Hagenbuch B (2011) Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos 39:920–926

    Article  PubMed  PubMed Central  Google Scholar 

  • Roth M, Obaidat A, Hagenbuch B (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Brit J Pharmacol 165:1260–1287

    Article  CAS  Google Scholar 

  • Russel FG, Masereeuw R, van Aubel RA (2002) Molecular aspects of renal anionic drug transport. Annu Rev Physiol 64:563–594

    Article  CAS  PubMed  Google Scholar 

  • Sai Y, Kaneko Y, Ito S, Mitsuoka K, Kato Y, Tamai I et al (2006) Predominant contribution of organic anion transporting polypeptide OATP-B (OATP2B1) to apical uptake of estrone-3-sulfate by human intestinal Caco-2 cells. Drug Metab Dispos 34:1423–1431

    Article  CAS  PubMed  Google Scholar 

  • Salazar DE, Schentag JJ, Corcoran GB (1992) Obesity as a risk factor in drug-induced organ injury. V. Toxicokinetics of gentamicin in the obese overfed rat. Drug Metab Dispos 20:402–406

    CAS  PubMed  Google Scholar 

  • Salphati L (2009) Transport-metabolism interplay. Mol Pharm 6:1629–1630

    Article  CAS  PubMed  Google Scholar 

  • Satlin LM, Amin V, Wolkoff AW (1997) Organic anion transporting polypeptide mediates organic anion/HCO3- exchange. J Biol Chem 272:26340–26345

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Iwanaga T, Mamada H, Ogihara T, Yabuuchi H, Maeda T et al (2008) Involvement of uric acid transporters in alteration of serum uric acid level by angiotensin II receptor blockers. Pharm Res 25:639–646

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Mamada H, Anzai N, Shirasaka Y, Nakanishi T, Tamai I (2010) Renal secretion of uric acid by organic anion transporter 2 (OAT2/SLC22A7) in human. Biol Pharm Bull 33:498–503

    Article  CAS  PubMed  Google Scholar 

  • Sato T, Mishima E, Mano N, Abe T, Yamaguchi H (2017) Potential drug interactions mediated by renal organic anion transporter OATP4C1. J Pharmacol Exp Ther 362:271–277

    Article  CAS  PubMed  Google Scholar 

  • Sauzay C, White-Koning M, Hennebelle I, Deluche T, Delmas C, Imbs DC et al (2016) Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug interaction between pazopanib and cisplatin. Pharmacol Res 110:89–95

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10

    Article  CAS  PubMed  Google Scholar 

  • Seitz T, Stalmann R, Dalila N, Chen J, Pojar S, Dos Santos Pereira JN et al (2015) Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1. Genome Med 7:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seki S, Kobayashi M, Itagaki S, Hirano T, Iseki K (2009) Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells. Biochim Biophys Acta 1788:911–917

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Ocheltree SM, Hu Y, Keep RF, Smith DE (2007) Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption and brain penetration in mice. Drug Metab Dispos 35:1209–1296

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Liu T, Morse BL, Zhao Y, Zhang Y, Qiu X et al (2015) Characterization of organic anion transporter 2 (SLC22A7): a highly efficient transporter for creatinine and species-dependent renal tubular expression. Drug Metab Dispos 43:984–993

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Dai J, Liu T, Cheng Y, Chen W, Freeden C et al (2016) Coproporphyrins I and III as Functional markers of OATP1B activity: in vitro and in vivo evaluation in preclinical species. J Pharmacol Exp Ther 357:382–393

    Article  CAS  PubMed  Google Scholar 

  • Shimakata T, Kamoshida S, Kawamura J, Ogane N, Kameda Y, Yanagita E et al (2016) Immunohistochemical expression profiles of solute carrier transporters in alpha-fetoprotein-producing gastric cancer. Histopathology 69:812–821

    Article  PubMed  Google Scholar 

  • Shirasaka Y, Shichiri M, Mori T, Nakanishi T, Tamai I (2013) Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions. J Pharm Sci 102:3418–3426

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y (2011) Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 26:220–227

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112:71–105

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug–drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 304:610–616

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Hirano M, Sato H, Sugiyama Y (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1: SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug–drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 311:228–236

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Nagamatsu Y, Wada S, Sugiyama Y, Horie T (2009) Long-lasting inhibition of the transporter-mediated hepatic uptake of sulfobromophthalein by cyclosporin a in rats. Drug Metab Dispos 37:1172–1178

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Takeuchi K, Nagamatsu Y, Wada S, Sugiyama Y, Horie T (2012) Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake. Drug Metab Pharmacokinet 27:368–378

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Maeda K, Ikejiri YK, Horie T, Sugiyama Y (2013a) Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos 34:45–78

    Article  CAS  PubMed  Google Scholar 

  • Shitara Y, Takeuchi K, Horie T (2013b) Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake. J Pharm Sci 102:3427–3435

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shu N, Hu M, Ling Z, Liu P, Wang F, Xu P et al (2016a) The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp 3a and SLCO1B1. Sci Rep 6:33072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shu N, Hu M, Liu C, Zhang M, Ling Z, Zhang J et al (2016b) Decreased exposure of atorvastatin in diabetic rats partly due to induction of hepatic Cyp 3a and Oatp 2. Xenobiotica 46:875–881

    Article  CAS  PubMed  Google Scholar 

  • Sleijfer DT, Offerman JJ, Mulder NH, Verweij M, van der Hem GK, Schraffordt Koops HS et al (1987) The protective potential of the combination of verapamil and cimetidine on cisplatin-induced nephrotoxicity in man. Cancer 60:2823–2282

    Article  CAS  PubMed  Google Scholar 

  • Smith DE, Hu Hu Y, Shen H, Nagaraja TN, Fenstermacher JD, Keep RF (2011) Distribution of glycylsarcosine and cefadroxil among cerebrospinal fluid, choroid plexus, and brain parenchyma after intracerebroventricular injection is markedly different between wild-type and Pept 2 null mice. J Cereb Blood Flow Metab 31:250–261

    Article  CAS  PubMed  Google Scholar 

  • Smith DE, Clémençon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications. Mol Asp Med 34:323–336

    Article  CAS  Google Scholar 

  • Sobin C, Flores-Montoya MG, Gutierrez M, Parisi N, Schaub T (2015) δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2∗2 haplotype (hPEPT2∗2) differently influence neurobehavior in low-level lead exposed children. Neurotoxicol Teratol 247:137–145

    Article  CAS  Google Scholar 

  • Song IS, Shin HJ, Shin JG (2008) Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes. Xenobiotica 38:1252–1262

    Article  CAS  PubMed  Google Scholar 

  • Sprowl JA, van Doorn L, Hu S, van Gerven L, de Bruijn P, Li L et al (2013) Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance. Clin Pharmacol Ther 94:585–592

    Article  CAS  PubMed  Google Scholar 

  • Sprowl S, Lancaster CS, Pabla N, Hermann E, Kosloske AM, Gibson AA et al (2014) Cisplatin- induced renal injury is independently mediated by OCT2 and p 53. Clin Cancer Res 20:4026–4035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stamer UM, Musshoff F, Stüber F, Brockmöller J, Steffens M, Tzvetkov MV (2016) Loss-of- function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption. Pain 157:2467–2475

    Article  CAS  PubMed  Google Scholar 

  • Staud F, Cerveny L, Ahmadimoghaddam D, Ceckova M (2013) Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics. Int J Biochem Cell Biol 45:2007–2011

    Article  CAS  PubMed  Google Scholar 

  • Stefanko E, Rybka J, Jaźwiec B, Haus O, Stąpor S, Kuliczkowski K et al (2017) Significance of OCT1 expression in acute myeloid leukemia. Pathol Oncol Res 23:665–671

    Article  CAS  PubMed  Google Scholar 

  • Stelzl T, Baranov T, Geillinger KE, Kottra G, Daniel H (2016) Effect of N-glycosylation on the transport activity of the peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 310:G128–G411

    Article  PubMed  Google Scholar 

  • Stelzl T, Geillinger-Kästle KE, Stolz J, Daniel H (2017) Glycans in the intestinal peptide transporter PEPT1 contribute to function and protect from proteolysis. Am J Physiol Gastrointest Liver Physiol 312:G580–G591

    Article  PubMed  Google Scholar 

  • Sticova E, Lodererova A, van de Steeg E, Frankova S, Kollar M, Lanska V et al (2015) Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis. Int J Clin Exp Pathol 8:5252–5262

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A et al (2013) The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 93:186–194

    Article  CAS  PubMed  Google Scholar 

  • Suga T, Yamaguchi H, Sato T, Maekawa M, Goto J, Mano N (2017) Preference of conjugated bile acids over unconjugated bile acids as substrates for OATP1B1and OATP1B3. PLoS One 12:e0169719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara M, Huang W, Fei YJ, Leibach FH, Ganapathy V, Ganapathy ME (2000) Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci 89:781–789

    Article  CAS  PubMed  Google Scholar 

  • Sun D, Wang Y, Tan F, Fang D, Hu Y, Smith DE et al (2013) Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human. Mol Pharm 10:1409–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sundelin EI, Gormsen LC, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL et al (2017) Genetic polymorphisms in organic cation transporter 1 attenuates hepatic metformin exposure in humans. Clin Pharmacol Ther 102:841–848

    Article  CAS  PubMed  Google Scholar 

  • Svoboda M, Wlcek K, Taferner B, Hering S, Stieger B, Tong D et al (2011) Expression of oranion-transporting polypeptides 1B1 and 1B3 in ovarian cancer cells: relevance for paclitaxel transport. Biomed Pharmacother 65:417–426

    Article  CAS  PubMed  Google Scholar 

  • Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara K, Kawamoto R, Nakura J et al (2004) Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metab Pharmacokinet 19:375–380

    Article  CAS  PubMed  Google Scholar 

  • Tachikawa M, Ozeki G, Higuchi T, Akanuma S, Tsuji K, Hosoya K (2012a) Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2 produced in the brain. J Neurochem 123:750–760

    Article  CAS  PubMed  Google Scholar 

  • Tachikawa M, Tsuji K, Yokoyama R, Higuchi T, Ozeki G, Yashiki A et al (2012b) A clearance system for prostaglandin D2, a sleep-promoting factor, in cerebrospinal fluid: role of the blood-cerebrospinal barrier transporters. J Pharmaacol Exp Ther 343:608–616

    Article  CAS  Google Scholar 

  • Tachikawa M, Hosoya K, Terasaki T (2014) Pharmacological significance of prostaglandin E2 and D2 transport at the brain barriers. Adv Pharmacol 71:337–360

    Article  CAS  PubMed  Google Scholar 

  • Taguchi T, Masuo Y, Kogi T, Nakamichi N, Kato Y (2016) Characterization of long-lasting Oatp inhibition by typical inhibitor cyclosporine a and in vitro-in vivo discrepancy in its drug interaction potential in rats. J Pharm Sci 105:2231–2239

    Article  CAS  PubMed  Google Scholar 

  • Tai W, Chen Z, Cheng K (2013) Expression profile and functional activity of peptide transporters in prostate cancer cells. Mol Pharm 10:477–487

    Article  CAS  PubMed  Google Scholar 

  • Takeda M, Narikawa S, Hosoyamada M, Cha SH, Sekine T, Endou H (2001) Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur J Pharmacol 419:113–120

    Article  CAS  PubMed  Google Scholar 

  • Takeda M, Babu E, Narikawa S, Endou H (2002) Interaction of human organic anion transporters with various cephalosporin antibiotics. Eur J Pharmacol 438:137–142

    Article  CAS  PubMed  Google Scholar 

  • Tamai I (2012) Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev 64:508–514

    Article  CAS  PubMed  Google Scholar 

  • Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M et al (2000) Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 273:251–260

    Article  CAS  PubMed  Google Scholar 

  • Tamai I, Nozawa T, Koshida M, Nezu J, Sai Y, Tsuji A (2001) Characterization of human organic anion polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res 18:1262–1269

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Tapaninen T, Neuvonen PJ, Niem M (2011) Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren. Br J Clin Pharmacol 71:718–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tashiro A, Tatsumi S, Takeda R, Naka A, Matsuoka H, Hashimoto Y et al (2014) High expression of organic anion transporter 2 and organic cation transporter 2 is an independent predictor of good outcomes in patients with metastatic colorectal cancer treated with FOLFOX-based chemotherapy. Am J Cancer Res 4:528–536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor-Wells J, Meredith D (2014) The signature sequence region of the human drug transporter organic anion transporting polypeptide 1B1 is important for protein surface expression. J Drug Deliv 2014:129849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tchernitchko D, Tavernier Q, Lamoril J, Schmitt C, Talbi N, Lyoumi S et al (2017) A variant of peptide transporter 2 predicts the severity of porphyria-associated kidney disease. J Am Soc Nephrol 28:1924–1932

    Article  CAS  PubMed  Google Scholar 

  • Te Brake LH, van den Heuvel JJ, Buaben AO, van Crevel R, Bilos A, Russel FG et al (2016) Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol. Antimicrob Agents Chemother 60:7105–7114

    Google Scholar 

  • Teft WA, Welch S, Lenehan J, Parfitt J, Choi YH, Winquist E et al (2015) OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy. Brit J Cancer 112:857–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Thakkar N, Kim K, Jang ER, Han S, Kim D, Merchant N, Lockhart AC, Lee W (2013) A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells. Mol Pharm 10:406–416

    Article  CAS  PubMed  Google Scholar 

  • Thwaites DT, Anderson CMH (2007) H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physio 92:603–619

    Article  CAS  Google Scholar 

  • Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276:35669–35675

    Article  CAS  PubMed  Google Scholar 

  • Tkáč L, Klimčáková L, Javorský M, Fabianová M, Schroner Z, Hermanová H et al (2013) Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes. Diabetes Obes Metab 15:189–191

    Article  CAS  PubMed  Google Scholar 

  • Töllner K, Brandt C, Römermann K, Löscher W (2015) The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide. Eur J Pharmacol 746:167–173

    Article  CAS  PubMed  Google Scholar 

  • Torres AM, Dnyanmote AV, Bush KT, Wu W, Nigam SK (2011) Deletion of multispecific organic anion transporter Oat 1/Slc 22a6 protects against mercury-induced kidney injury. J Biol Chem 286:26391–26395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toyama K, Yonezawa A, Tsuda M, Masuda S, Yano I, Terada T et al (2010) Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients. Pharmacogenet Genomics 20:135–138

    Article  CAS  PubMed  Google Scholar 

  • Toyama K, Yonezawa A, Masuda S, Osawa R, Hosokawa M, Fujimoto S et al (2011) Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Brit J Pharmacol 166:1183–1191

    Article  CAS  Google Scholar 

  • Tsuda M, Terada T, Asaka J, Ueba M, Katsura T, Inui K (2007) Oppositely directed H+ gradient functions as a driving force of rat H+/organic cation antiporter MATE1. Am J Physiol Renal Physiol 292:F593–F598

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Tu M, Sun S, Wang K, Peng X, Wang R, Li L et al (2013) Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity. Toxicology 311:225–230

    Article  CAS  PubMed  Google Scholar 

  • Tu M, Li L, Lei H, Ma Z, Chen Z, Sun S et al (2014) Involvement of organic cation transporter 1 and CYP3A4 in retrorsine-induced toxicity. Toxicology 322:34–42

    Article  CAS  PubMed  Google Scholar 

  • Tyce GM (1990) Origin and metabolism of serotonin. J Cardiovasc Pharmacol 16(Suppl 3):S1–S7

    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 90:143–150

    Article  CAS  PubMed  Google Scholar 

  • Tzvetkov MV, dos Santos Pereira JN, Meineke I, Saadatmand AR, Stingl JC et al (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

    Article  CAS  PubMed  Google Scholar 

  • Umamaheswaran G, Praveen RG, Damodaran SE, Das AK, Adithan C (2015) Influence of SLC22A1 rs 622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients. Clin Exp Med 15:511–517

    Article  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 

  • Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K (2007) Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 24:811–815

    Article  CAS  PubMed  Google Scholar 

  • Uwai Y, Honjo H, Iwamoto K (2012) Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacol Res 65:254–260

    Article  CAS  PubMed  Google Scholar 

  • Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK (2008a) Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol 294:F867–F873

    Article  CAS  PubMed  Google Scholar 

  • Vallon V, Eraly SA, Wikoff WR, Rieg T, Kaler G, Truong DM et al (2008b) Organic anion t ransporter 3 contributes to the regulation of blood pressure. J Am Soc Nephrol 19:1732–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E et al (2012) Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrom by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122:519–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varma MV, Rotter CJ, Chupka J, Whalen KM, Duignan DB, Feng B et al (2011) pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm 8:1303–1313

    Article  CAS  PubMed  Google Scholar 

  • Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K, Waypa TS et al (2004) hPepT1 transports muramyl dipeptide, activating NF-kappa B and stimulating IL-8 secretion in human colonic Caco 2/bbe cells. Gastroenterology 127:1401–1409

    Article  CAS  PubMed  Google Scholar 

  • Vavricka SR, Musch MW, Fujiya M, Kles K, Chang L, Eloranta JJ et al (2006) Tumor necrosis factor-alpha and interferon-gamma increase Pep T1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine. Pflugers Arch 452:71–80

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Viennois E, Ingersoll SA, Ayyadurai S, Zhao Y, Wang L, Zhang M et al (2016) Critical role of PEPT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PEPT1-mediated tripeptide KPV in a murine model. Cell Mol Gastroenterol Hepatol 2:340–357

    Article  PubMed  PubMed Central  Google Scholar 

  • Vildhede A, Karlgren M, Svedberg EK, Wisniewski JR, Lai Y, Norén A et al (2014) Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos 42:1210–1218

    Article  CAS  PubMed  Google Scholar 

  • Visentin M, Chang MH, Romero MF, Zhao R, Goldman ID (2012) Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol 81:134–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA et al (2009) The SLCO1B1∗5 genetic variant is associated with statin induced side effects. J Am Coll Cardiol 54:1609–1616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Wolkoff AW, Morris ME (2005) Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab Dispos 33:1666–1672

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Uray IP, Mazumdar A, Mayer JA, Brown PH (2012) SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen-response element (ERE). Breast Cancer Res Treat 134:101–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Wang C, Liu Q, Meng Q, Huo X, Sun P et al (2014) PEPT1- and OAT1/3-mediated drug-drug interactions between bestatin and cefixime in vivo and in vitro in rats, and in vitro in human. Eur J Pharm Sci 63:77–86

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Kusuhara H, Maeda K, Kanamaru H, Saito Y, Hu Z et al (2010a) Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans. Drug Metab Dispos 38:215–222

    Article  CAS  PubMed  Google Scholar 

  • Watanabe S, Tsuda M, Terada T, Katsura T, Inui K (2010b) Reduced renal clearance of a zwitterionic substrate cephalexin in MATE1-deficient mice. J Pharmacol Exp Ther 334:651–656

    Article  CAS  PubMed  Google Scholar 

  • Weaver YM, Hagenbuch B (2010) Several conserved positively charged amino acids in OATP1B1 are involved in binding or translocation of different substrates. J Membr Biol 236:279–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weleber RG, Shults WT (1981) Digoxin retinal toxicity. Clinical and electrophysiological evaluation of a cone dysfunction syndrome. Arch Ophthalmol 99:1568–1572

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X et al (2013) Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem 56:781–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu SP, Smith DE (2013) Impact of intestinal Pep T1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide. Mol Pharm 10:677–684

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Dnyanmote AV, Nigam SK (2011) Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. Mol Pharmacol 79:795–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Jamshidi N, Eraly SA, Liu HC, Bush KT, Palsson BO et al (2013) Multispecific drug transporter Slc 22a8 (Oat 3) regulates multiple metabolic and signaling pathways. Drug Metab Dispos 41:1825–1834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu KC, Lu YH, Peng YH, Tsai TF, Kao YH, Yang HT, Lin CJ (2015a) Decreased expression of organic cation transporters, Oct 1 and Oct 2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice. J Cereb Blood Flow Metab 35:37–47

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Zhang J, Liu H, Mian Y, Liang B, Xie H et al (2015b) Organic anion transporter 1 deficiency accelerates learning and memory impairment in tg 2576 mice by damaging dendritic spine morphology and activity. J Mol Neurosci 56:730–738

    Article  CAS  PubMed  Google Scholar 

  • Wuensch T, Schulz S, Ullrich S, Lill N, Stelzl T, Rubio-Aliaga I et al (2013) The peptide transporter PEPT1 is expressed in distal colon in rodents and humans and contributes, to water absorption. Am J Physiol Gastrointest Liver Physiol 305:G66–G73

    Article  CAS  PubMed  Google Scholar 

  • Wuensch T, Ullrich S, Schulz S, Chamaillard M, Schaltenberg N, Rath E et al (2014) Colonic expression of the peptide transporter PEPT1 is downregulated during intestinal inflammation and is not required for NOD2-dependent immune activation. Inflamm Bowel Dis 20:671–684

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Xiao D, Guo Y, Li X, Yin JY, Zheng W, Qiu XW et al (2016) The impacts of SLC22A1 rs 594709 and SLC47A1 rs 2289669 polymorphisms on metformin therapeutic efficacy in Chinese type 2 diabetes patients. Int J Endocrinol 2016:4350712

    PubMed  PubMed Central  Google Scholar 

  • Xu D, Zhang J, Zhang M, Mei D, Liu XD (2013) Pharmacokinetics roles of organic transporting polypeptides. J Chin Pharmacet Uni 44:482–486

    CAS  Google Scholar 

  • Xu D, Li F, Zhang M, Zhang J, Liu C, Hu MY et al (2014) Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes. Acta Pharmacol Sin 35:1215–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu C, Zhu L, Chan T, Lu X, Shen W, Madigan MC et al (2016) Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2. J Pharm Sci 105:884–890

    Article  CAS  PubMed  Google Scholar 

  • Xue X, Gong LK, Maeda K, Luan Y, Qi XM, Sugiyama Y et al (2011) Critical role of organic anion transporters 1 and 3 in kidney accumulation and toxicity of aristolochic acid I. Mol Pharm 8:2183–2192

    Article  CAS  PubMed  Google Scholar 

  • Yamada A, Maeda K, Kamiyama E, Sugiyama D, Kondo T, Shiroyanagi Y et al (2007) Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos 35:2166–2176

    Article  CAS  PubMed  Google Scholar 

  • Yamashiro W, Maeda K, Hirouchi M, Adachi Y, Hu Z, Sugiyama Y (2006) Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos 34:1247–1254

    Article  CAS  PubMed  Google Scholar 

  • Yan Z, Sun J, Chang Y, Liu Y, Fu Q, Xu Y et al (2011) Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics. Mol Pharm 8:319–329

    Article  CAS  PubMed  Google Scholar 

  • Yang B, Smith DE (2013) Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PEPT1 knockout mice. Drug Metab Dispos 41:608–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang B, Hu Y, Smith DE (2013) Impact of Peptide Transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PEPT1 knockout mice. Drug Metab Dispos 41:1867–1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Guo D, Obianom ON, Su T, Polli JE, Shu Y (2017) Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. Toxicol Appl Pharmacol 314:55–62

    Article  CAS  PubMed  Google Scholar 

  • Yaylali SA, Sadigov F, Erbil H, Ekinci A, Akcakaya AA (2013) Chloroquine and hydroxychloroquine retinopathy-related risk factors in a Turkish cohort. Int Ophthalmol 33:627–634

    Article  PubMed  Google Scholar 

  • Ye J, Liu Q, Wang C, Meng Q, Sun H, Peng J, Ma X, Liu K (2013) Benzylpenicillin inhibits the renal excretion of acyclovir by OAT1 and OAT3. Pharmacol Rep 65:505–512

    Article  CAS  PubMed  Google Scholar 

  • Yeh YC, Huang MF, Liang SS, Hwang SJ, Tsai JC, Liu TL et al (2016) Indoxyl sulfate, not p-cresyl sulfate, is associated with cognitive impairment in early-stage chronic kidney disease. Neurotoxicology 53:148–152

    Article  CAS  PubMed  Google Scholar 

  • Yin OQ, Tomlinson B, Chow MS (2006) Variability in renal clearance of substrates for renal transporters in Chinese subjects. J Clin Pharmacol 46:157–163

    Article  CAS  PubMed  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 43:1872–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin J, Duan H, Wang J (2016) Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation. J Pharmacol Exp Ther 359:401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokoo S, Yonezawa A, Masuda S, i Fukatsu A, Katsura T, Inui KI (2007) Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharamcol 74:477–487

    Article  CAS  Google Scholar 

  • Yonezawa A, Inui K (2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Brit J Pharmacol 164:1817–1825

    Article  CAS  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

    Article  CAS  PubMed  Google Scholar 

  • Zaïr ZM, Eloranta JJ, Stieger B, Kullak-Ublick GA (2008) Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics 9:597–624

    Article  PubMed  Google Scholar 

  • Zhang J, Zhou W (2012) Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. Food Chem Toxicol 50:2289–2293

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Chen BL, Ozdemir V, He YJ, Zhou G, Peng DD et al (2007) SLCOB1 521T>C functional genetic polymorphism and lipid-lowering efficacy of multiple-dose pravastatin in Chinese coronary heart disease patients. Br J Clin Pharmacol 64:346–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Sun J, Gao Y, Jin L, Xu Y, Lian H et al (2013) A carrier-mediated prodrug approach to improve the oral absorption of antileukemic drug decitabine. Mol Pharm 10:3195–3202

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Warren MS, Zhang X, Diamond S, Williams B, Punwani N et al (2015) Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110. Drug Metab Dispos 43:485–489

    Article  CAS  PubMed  Google Scholar 

  • Zhou Q, Liao JK (2010) Pleiotropic effects of statins: basic research and clinical perspectives. Circ J 74:818–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Yuan J, Li Z, Wang Z, Cheng D, Du Y et al (2015) Genetic polymorphisms and function of the organic anion-transporting polypeptide 1A2 and its clinical relevance in drug disposition. Pharmacology 95:201–208

    Article  CAS  PubMed  Google Scholar 

  • Zhou F, Zhu L, Wang K, Murray M (2017) Recent advance in the pharmacogenomics of human solute carrier 2 transporters (SLCs) in drug disposition. Adv Drug Deliv Rev 116:21–36

    Article  CAS  PubMed  Google Scholar 

  • Zhu HJ, Appela DI, Gründemannc D, Richelsond E, Markowitz JS (2012) Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action. Pharmacol Res 65:491–496

    Article  CAS  PubMed  Google Scholar 

  • Ziegler TR, Fernandez-Estivariz C, Gu LH, Bazargan N, Umeakunne K, Wallace TM et al (2002) Distribution of the H+/peptide transporter PEPT1 in human intestine: upregulated expression in the colonic mucosa of patients with short-bowel syndrome. Am J Clin Nutr 75:922–930

    Article  CAS  PubMed  Google Scholar 

  • Zimmerman EL, Hu S, Roberts JL, Gibson AA, Orwick SJ, Li L et al (2013) Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res 19:1458–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The project was in part supported by the National Natural Science Foundation of China (No. 81872930; 81573490) and “Double First-Class” University project (No. CPU2018GY22).

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Liu, X. (2019). SLC Family Transporters. In: Liu, X., Pan, G. (eds) Drug Transporters in Drug Disposition, Effects and Toxicity. Advances in Experimental Medicine and Biology, vol 1141. Springer, Singapore. https://doi.org/10.1007/978-981-13-7647-4_3

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