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Review Article

Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects

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Pages 380-401 | Accepted 17 Nov 2009, Published online: 25 Jan 2010

References

  • Abe, T., Kakyo, M., Tokui, T., Nakagomi, R., Nishio, T., Nakai, D., et al. (1999). Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 274:17159–17163.
  • Abe, T., Unno, M., Onogawa, T., Tokui, T., Kondo, T. N., Nakagomi, R., et al. (2001). LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 120:1689–1699.
  • Allikmets, R., Gerrard, B., Hutchinson, A., Dean, M. (1996). Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 5:1649–1655.
  • Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I., Gottesman, M. M. (1999). Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398.
  • Anzai, N., Kanai, Y., Endou, H. (2006). Organic anion transporter family: current knowledge. J Pharmacol Sci 100:411–426.
  • Aoki, M., Terada, T., Ogasawara, K., Katsura, T., Hatano, E., Ikai, I., et al. (2009). Impact of regulatory polymorphisms in organic anion transporter genes in the human liver. Pharmacogenet Genom 19:647–656.
  • Bachmakov, I., Glaeser, H., Fromm, M. F., König, J. (2008). Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion-transporting polypeptides and organic cation transporter 1. Diabetes 57:1463–1469.
  • Backman, J. T., Kyrklund, C., Kivistö, K. T., Wang, J. S., Neuvonen, P. J. (2000). Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 68:122–129.
  • Backman, J. T., Kyrklund, C., Neuvonen, M., Neuvonen, P. J. (2002). Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 72:685–691.
  • Batt, A. M., Magdalou, J., Vincent-Viry, M., Ouzzine, M., Fournel-Gigleux, S., Galteau, M. M., et al. (1994). Drug-metabolizing enzymes related to laboratory medicine: cytochromes P450 and UDP-glucuronosyltransferases. Clin Chim Acta 226:171–190.
  • Briz, O., Macias, R. I., Serrano, M. A., Gonzalez-Gallego, J., Bayon, J. E., Marin, J. J. (2003a). Excretion of foetal bilirubin by the rat placenta-maternal liver tandem. Placenta 24:462–472.
  • Briz, O., Serrano, M. A., MacIas, R. I., Gonzalez-Gallego, J., Marin, J. J. (2003b). Role of organic anion-transporting polypeptides OATP-A, OATP-C, and OATP-8 in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J 371:897–905.
  • Chung, J. Y., Cho, J. Y., Yu, K. S., Kim, J. R., Oh, D. S., Jung, H. R., et al. (2005). Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 78:342–350.
  • Choi, J.H., Lee, M.G., Cho, J.-Y., Lee, J.-E., Kim, K.H., Park, K.(2008). Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther 83(2):251–7.
  • Couvert, P., Giral, P., Dejager, S., Gu, J., Huby, T., Chapman, M.J., Bruckert, E., et al.(2008). Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy. Pharmacogenomics 9(9):1217–27.
  • Cui, Y., König, J., Keppler, D. (2001a). Vectorial transport by double-transfected cells expressing the human uptake transporter, SLC21A8, and the apical export pump ABCC2. Mol Pharmacol 60:934–943.
  • Cui, Y., König, J., Leier, I., Buchholz, U., Keppler, D. (2001b). Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter, SLC21A6. J Biol Chem 276:9626–9630.
  • Deng, J.W., Song, I.-S., Shin, H.J., Yeo, C.-W., Cho, D.-Y., Shon, J.-H., Shin, J.-G.(2008). The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genomics 18(5):424–33.
  • Elens, L., Capron, A., Kerckhove, V. V., Lerut, J., Mourad, M., Lison, D., et al. (2007). 1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation. Pharmacogenet Genom 17:873–883.
  • Enomoto, A., Kimura, H., Chairoungdua, A., Shigeta, Y., Jutabha, P., Cha, S. H., et al. (2002). Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 417:447–452.
  • Fuchikami, H., Satoh, H., Tsujimoto, M., Ohdo, S., Ohtani, H., Sawada, Y. (2006). Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab Dispos 34:577–582.
  • Gerloff, T., Schaefer, M., Mwinyi, J., Johne, A., Sudhop, T., Lutjohann, D., et al. (2006). Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin’s cholesterol lowering capabilities and basal sterol serum levels. Naunyn Schmiedebergs Arch Pharmacol 373:45–50.
  • Gorboulev, V., Ulzheimer, J. C., Akhoundova, A., Ulzheimer-Teuber, I., Karbach, U., Quester, S., et al. (1997). Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881.
  • Grube, M., Kock, 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.
  • Hagenbuch, B., Meier, P. J. (2003). The superfamily of organic anion-transporting polypeptides. Biochim Biophys Acta 1609:1–18.
  • Hagenbuch, B., Meier, P. J. (2004). Organic anion-transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature, and molecular/functional properties. Pflug Arch 447:653–665.
  • Han, J.-Y., Lim, H.-S., Shin, E.S., Yoo, Y.-K., Park, Y.H., Lee, J.-E., Kim, H. T., et al.(2007). Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer 59(1):69–75.
  • Hediger, M. A., Romero, M. F., Peng, J. B., Rolfs, A., Takanaga, H., Bruford, E. A. (2004). The ABCs of solute carriers: physiological, pathological, and therapeutic implications of human membrane transport proteins [Introduction]. Pflug Arch 447:465–468.
  • Hedman, M., Antikainen, M., Holmberg, C., Neuvonen, M., Eichelbaum, M., Kivistö, K.T., Neuvonen, P.J., et al.(2006). Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes. Br J Clin Pharmacol 61(6):706–15.
  • 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.
  • Ho, R. H., Tirona, R. G., Leake, B. F., Glaeser, H., Lee, W., Lemke, C. J., et al. (2006). Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806.
  • Hosoyamada, M., Sekine, T., Kanai, Y., Endou, H. (1999). Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol 276:F122–F128.
  • Hsiang, B., Zhu, Y., Wang, Z., Wu, Y., Sasseville, V., Yang, W. P., et al. (1999). A novel human hepatic organic anion-transporting polypeptide (OATP2). Identification of a liver-specific human organic anion-transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274:37161–37168.
  • Hu, S., Franke, R. M., Filipski, K. K., Hu, C., Orwick, S. J., de Bruijn, E. A., et al. (2008). Interaction of imatinib with human organic ion carriers. Clin Cancer Res 14:3141–3148.
  • Ieiri, I., Suwannakul, S., Maeda, K., Uchimaru, H., Hashimoto, K., Kimura, M., Fujino, H., et al.(2007). SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 82(5):541–7.
  • Ieiri, I., Higuchi, S., Sugiyama, Y. (2009). Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for interindividual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Exp Opin Drug Metab Toxicol 5:703–729.
  • Igel, M., Arnold, K. A., Niemi, M., Hofmann, U., Schwab, M., Lutjohann, D., et al. (2006). Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin. Clin Pharmacol Ther 79:419–426.
  • Iida, A., Saito, S., Sekine, A., Mishima, C., Kondo, K., Kitamura, Y., et al. (2001). Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet 46:668–683.
  • 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.
  • Ito, K., Ogihara, K., Kanamitsu, S., Itoh, T. (2003). Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes. Drug Metab Dispos 31:945–954.
  • Itoda, M., Saito, Y., Maekawa, K., Hichiya, H., Komamura, K., Kamakura, S., et al. (2004). Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1). Drug Metab Pharmacokinet 19:308–312.
  • Iwai, M., Suzuki, H., Ieiri, I., Otsubo, K., Sugiyama, Y. (2004). Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C). Pharmacogenetics 14:749–757.
  • Jacobson, T. A. (2004). Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 94:1140–1146.
  • Johnson, A. D., Kavousi, M., Smith, A. V., Chen, M. H., Dehghan, A., Aspelund, T., et al. (2009). Genomewide-association meta-analysis for total serum bilirubin levels. Hum Mol Genet 18:2700–2710.
  • Jung, N., Lehmann, C., Rubbert, A., Knispel, M., Hartmann, P., van Lunzen, J. et, al. (2008). Relevance of the organic cation transporters, 1 and 2, for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 36:1616–1623.
  • Kalliokoski, A., Backman, J. T., Neuvonen, P. J., Niemi, M. (2008a). Effects of the SLCO1B1*1B haplotype on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. Pharmacogenet Genom 18:937–942.
  • Kalliokoski, A., Neuvonen, M., Neuvonen, P. J., Niemi, M. (2008b). Different effects of SLCO1B1 polymorphism on the pharmacokinetics and pharmacodynamics of repaglinide and nateglinide. J Clin Pharmacol 48:311–321.
  • Kalliokoski, A., Neuvonen, M., Neuvonen, P.J., Niemi, M.(2008c). The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range. Br J Clin Pharmacol 66(6):818–25.
  • Kameyama, Y., Yamashita, K., Kobayashi, K., Hosokawa, M., Chiba, K. (2005). Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15, and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genom 15:513–522.
  • Katz, D. A., Carr, R., Grimm, D. R., Xiong, H., Holley-Shanks, R., Mueller, T., et al. (2006). Organic anion-transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics. Clin Pharmacol Ther 79:186–196.
  • Kekuda, R., Prasad, P. D., Wu, X., Wang, H., Fei, Y. J., Leibach, F. H., et al. (1998). Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 273:15971–15979.
  • Keppler, D., Kamisako, T., Leier, I., Cui, Y., Nies, A. T., Tsujii, H., et al. (2000). Localization, substrate specificity, and drug resistance conferred by conjugate export pumps of the MRP family. Adv Enz Regul 40:339–349.
  • 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.
  • Kim, D. H., Sriharsha, L., Xu, W., Kamel-Reid, S., Liu, X., Siminovitch, K., et al. (2009). Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res 15:4750–4758.
  • Kindla, J., Fromm, M. F., König, J. (2009). In vitro evidence for the role of OATP and OCT uptake transporters in drug-drug interactions. Exp Opin Drug Metab Toxicol 5:489–500.
  • Kiyotani, K., Mushiroda, T., Kubo, M., Zembutsu, H., Sugiyama, Y., Nakamura, Y. (2008). Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. Cancer Sci 99:967–972.
  • Koepsell, H., Endou, H. (2004). The SLC22 drug transporter family. Pflug Arch 447:666–676.
  • Koepsell, H., Lips, K., Volk, C. (2007). Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251.
  • König, J., Cui, Y., Nies, A. T., Keppler, D. (2000a). Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275:23161–23168.
  • König, J., Cui, Y., Nies, A. T., Keppler, D. (2000b). A novel human organic anion-transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278:G156–G164.
  • König, J., Seithel, A., Gradhand, U., Fromm, M. F. (2006). Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol 372:432–443.
  • Kopplow, K., Letschert, K., König, J., Walter, B., Keppler, D. (2005). Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol 68:1031–1038.
  • Kruh, G. D., Belinsky, M. G. (2003). The MRP family of drug efflux pumps. Oncogene 22:7537–7552.
  • Kullak-Ublick, G. A., Ismair, M. G., 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.
  • Kusuhara, H., Sugiyama, Y. (2002). Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain, and kidney. J Contr Rel 78:43–54.
  • Kyrklund, C., Backman, J. T., Neuvonen, M., Neuvonen, P. J. (2003). Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 73:538–544.
  • Lee, E., Ryan, S., Birmingham, B., Zalikowski, J., March, R., Ambrose, H., et al. (2005). Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 78:330–341.
  • Letschert, K., Keppler, D., König, J. (2004). Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter, OATP1B3 (OATP8). Pharmacogenetics 14:441–452.
  • Link, E., Parish, S., Armitage, J., Bowman, L., Heath, S., Matsuda, F., et al. (2008). SLCO1B1 variants and statin-induced myopathy—a genomewide study. NEJM 359:789–799.
  • Maeda, K., Ieiri, I., Yasuda, K., Fujino, A., Fujiwara, H., Otsubo, K., et al. (2006a). Effects of organic anion-transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79:427–439.
  • Maeda, K., Kambara, M., Tian, Y., Hofmann, A. F., Sugiyama, Y. (2006b). Uptake of ursodeoxycholate and its conjugates by human hepatocytes: role of Na(+)-taurocholate cotransporting polypeptide (NTCP), organic anion-transporting polypeptide (OATP) 1B1 (OATP-C), and oatp1B3 (OATP8). Mol Pharm 3:70–77.
  • Matsushima, S., Maeda, K., Hayashi, H., Debori, Y., Schinkel, A. H., Schuetz, J. D., et al. (2008). Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol 73:1474–1483.
  • Michalski, C., Cui, Y., Nies, A. T., Nuessler, A. K., Neuhaus, P., Zanger, U. M., Klein, K., et al. (2002). A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 277:43058–43063.
  • Miura, M., Satoh, S., Inoue, K., Kagaya, H., Saito, M., Inoue, T., et al. (2007). Influence of SLCO1B1, 1B3, 2B1, and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63:1161–1169.
  • Morimoto, K., Oishi, T., Ueda, S., Ueda, M., Hosokawa, M., Chiba, K. (2004). A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet 19:453–455.
  • Mougey, E. B., Feng, H., Castro, M., Irvin, C. G., Lima, J. J. (2009). Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genom 19:129–138.
  • Muirhead, M., Bochner, F., Somogyi, A. (1988). Pharmacokinetic drug interactions between triamterene and ranitidine in humans: alterations in renal and hepatic clearances and gastrointestinal absorption. J Pharmacol Exp Ther 244:734–739.
  • 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.
  • Nakagomi-Hagihara, R., Nakai, D., Kawai, K., Yoshigae, Y., Tokui, T., Abe, T., et al. (2006). OATP1B1, OATP1B3, and mrp2 are involved in hepatobiliary transport of olmesartan, a novel angiotensin II blocker. Drug Metab Dispos 34:862–869.
  • Neuvonen, P. J., Backman, J. T., Niemi, M. (2008). Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin, and pravastatin. Clin Pharmacokinet 47:463–474.
  • Neuvonen, P. J., Kantola, T., Kivistö, K. T. (1998). Simvastatin, but not pravastatin, is very susceptible to interaction with the CYP3A4 inhibitor, itraconazole. Clin Pharmacol Ther 63:332–341.
  • Neuvonen, P. J., Niemi, M., Backman, J. T. (2006). Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80:565–581.
  • Niemi, M., Backman, J. T., Kajosaari, L. I., Leathart, J. B., Neuvonen, M., Daly, A. K., et al. (2005a). Polymorphic organic anion-transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 77:468–478.
  • Niemi, M., Kivistö, K. T., Hofmann, U., Schwab, M., Eichelbaum, M., Fromm, M. F. (2005b). Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). Br J Clin Pharmacol 59:602–604.
  • Niemi, M., Neuvonen, P. J., Hofmann, U., Backman, J. T., Schwab, M., Lutjohann, D., et al. (2005c). Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet Genom 15:303–309.
  • Niemi, M., Pasanen, M. K., Neuvonen, P. J. (2006). SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther 80:356–366.
  • Niemi, M., Schaeffeler, E., Lang, T., Fromm, M. F., Neuvonen, M., Kyrklund, C., et al. (2004). High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion-transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440.
  • Nies, A. T., 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. [Epub May 28].
  • 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.
  • Noe, J., Portmann, R., Brun, M. E., 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.
  • Nozawa, T., Imai, K., Nezu, J., Tsuji, A., Tamai, I. (2004a). Functional characterization of pH-sensitive organic anion-transporting polypeptide, OATP-B, in humans. J Pharmacol Exp Ther 308:438–445.
  • Nozawa, T., Minami, H., Sugiura, S., Tsuji, A., Tamai, I. (2005). Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33:434–439.
  • Nozawa, T., Nakajima, M., Tamai, I., Noda, K., Nezu, J., Sai, Y., et al. (2002). Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813.
  • Nozawa, T., Sugiura, S., Nakajima, M., Goto, A., Yokoi, T., Nezu, J., et al. (2004c). Involvement of organic anion-transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos 32:291–294.
  • Okudaira, N., Sugiyama, Y. (1996). Use of an isolated perfused kidney to assess renal clearance of drugs: information obtained in steady-state and non-steady-state experimental systems. Pharm Biotechnol 8:211–238.
  • Omote, H., Hiasa, M., Matsumoto, T., Otsuka, M., Moriyama, Y. (2006). The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations. Trends Pharmacol Sci 27:587–593.
  • Oostendorp, R. L., van de Steeg, E. van, der Kruijssen, C. M., Beijnen, J. H., Kenworthy, K. E., Schinkel, A. H., et al. (2009). Organic anion-transporting polypeptide 1B1 mediates transport of gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors. Drug Metab Dispos 37:917–923.
  • Oswald, S., König, J., Lutjohann, D., Giessmann, T., Kroemer, H. K., Rimmbach, C., et al. (2008). Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier, OATP1B1. Pharmacogenet Genom 18:559–568.
  • Pasanen, M. K., Fredrikson, H., Neuvonen, P. J., Niemi, M. (2007). Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82:726–733.
  • Pasanen, M. K., Neuvonen, M., Neuvonen, P. J., Niemi, M. (2006). SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genom 16:873–879.
  • Petzinger, E. (1994). Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport. Rev Physiol Biochem Pharmacol 123:47–211.
  • Polasek, T. M., Miners, J. O. (2006). Quantitative prediction of macrolide drug-drug interaction potential from in vitro studies using testosterone as the human cytochrome P4503A substrate. Eur J Clin Pharmacol 62:203–208.
  • Rizwan, A. N., Burckhardt, G. (2007). Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm Res 24:450–470.
  • Sakata, T., Anzai, N., Shin, H. J., Noshiro, R., Hirata, T., Yokoyama, H., et al. (2004). Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun 313:789–793.
  • Sandhu, P., Lee, W., Xu, X., Leake, B. F., Yamazaki, M., Stone, J. A., et al. (2005). Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos 33:676–682.
  • Sanna, S., Busonero, F., Maschio, A., McArdle, P. F., Usala, G., Dei, M., et al. (2009). Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. Hum Mol Genet 18:2711–2718.
  • Sato, T., Masuda, S., Yonezawa, A., Tanihara, Y., Katsura, T., Inui, K. (2008). Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1. Biochem Pharmacol 76:894–903.
  • Schneck, D. W., Birmingham, B. K., Zalikowski, J. A., Mitchell, P. D., Wang, Y., Martin, P. D., et al. (2004). The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75:455–463.
  • Schwenk, M. (1987). Drug transport in intestine, liver, and kidney. Arch Toxicol 60:37–42.
  • Seithel, A., Eberl, S., Singer, K., Auge, D., Heinkele, G., Wolf, N. B., et al. (2007). The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos 35:779–786.
  • Sekine, T., Cha, S. H., Tsuda, M., Apiwattanakul, N., Nakajima, N., Kanai, Y., et al. (1998). Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 429:179–182.
  • Shimizu, M., Fuse, K., Okudaira, K., Nishigaki, R., Maeda, K., Kusuhara, H., Sugiyama, Y. (2005). Contribution of OATP (organic anion-transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos 33:1477–1481.
  • Shin, H. J., Anzai, N., Enomoto, A., He, X., Kim, D. K., Endou, H., et al. (2007). Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short-chain fatty acid butyrate. Hepatology 45:1046–1055.
  • 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.
  • Shu, Y., Brown, C., Castro, R. A., Shi, R. J., Lin, E. T., Owen, R. P., et al. (2007a). Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280.
  • Shu, Y., Leabman, M. K., Feng, B., Mangravite, L. M., Huang, C. C., Stryke, D., et al. (2003). Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A 100:5902–5907.
  • Shu, Y., Sheardown, S. A., Brown, C., Owen, R. P., Zhang, S., Castro, R. A., et al. (2007b). Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431.
  • Smith, N. F., Acharya, M. R., Desai, N., Figg, W. D., Sparreboom, A. (2005). Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 4:815–818.
  • Smith, N. F., Marsh, S., Scott-Horton, T. J., Hamada, A., Mielke, S., Mross, K., et al. (2007). Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharmacol Ther 81:76–82.
  • Somogyi, A., Bochner, F. (1984). Dose- and concentration-dependent effect of ranitidine on procainamide disposition and renal clearance in man. Br J Clin Pharmacol 18:175–181.
  • St-Pierre, M. V., Hagenbuch, B., Ugele, B., Meier, P. J., Stallmach,T. (2002). Characterization of an organic anion-transporting polypeptide (OATP-B) in human placenta. J Clin Endocrinol Metab 87:1856–1863.
  • Sun, W., Wu, R. R., van Poelje, P. D., Erion, M. D. (2001). Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun 283:417–422.
  • Suwannakul, S., Ieiri, I., Kimura, M., Kawabata, K., Kusuhara, H., Hirota, T., Irie, S., et al.(2008). Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism. J Hum Genet 53(10):899–904.
  • Suzuki, H., Sugiyama, Y. (2000). Transport of drugs across the hepatic sinusoidal membrane: sinusoidal drug influx and efflux in the liver. Semin Liver Dis 20:251–263.
  • 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.
  • Takane, H., Miyata, M., Burioka, N., Shigemasa, C., Shimizu, E., Otsubo, K., et al. (2006). Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy. J Hum Genet 51:822–826.
  • Takane, H., Shikata, E., Otsubo, K., Higuchi, S., Ieiri, I. (2008). Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics 9:415–422.
  • Takeuchi, A., Motohashi, H., Okuda, M., Inui, K. (2003). Decreased function of genetic variants, Pro283Leu and Arg287Gly, in human organic cation transporter hOCT1. Drug Metab Pharmacokinet 18:409–412.
  • 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.
  • Tamai, I., Nozawa, T., Koshida, M., Nezu, J., Sai, Y., Tsuji, A. (2001). Functional characterization of human organic anion-transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res 18:1262–1269.
  • Tamai, I., Yabuuchi, H., Nezu, J., Sai, Y., Oku, A., Shimane, M., et al. (1997). Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett 419:107–111.
  • Tirona, R. G., Leake, B. F., Merino, G., Kim, R. B. (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.
  • Tirona, R. G., Leake, B. F., Wolkoff, A. W., Kim, R. B. (2003). Human organic anion-transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304:223–228.
  • Treiber, A., Schneiter, R., Hausler, S., Stieger, B. (2007). Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos 35:1400–1407.
  • Tsuda-Tsukimoto, M., Maeda, T., Iwanaga, T., Kume, T., Tamai, I.(2006). Characterization of hepatobiliary transport systems of a novel a4b1/a4b7 dual antagonist, TR-14035. Pharm Res 23(11):2646–56.
  • Tzvetkov, M. V., Vormfelde, S. V., Balen, D., Meineke, I., Schmidt, T., Sehrt, D., et al. (2009). The effects of genetic polymorphisms in the organic cation transporters, OCT1, OCT2, and OCT3, on the renal clearance of metformin. Clin Pharmacol Ther 86:299–306. [Epub Jun 17].
  • Umehara, K., Shirai, N., Iwatsubo, T., Noguchi, K., Usui, T., Kamimura, H. (2009). Identification of human metabolites of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, and investigation of the transporter-mediated renal and hepatic excretion of these metabolites. Drug Metab Dispos 37:1646–1657.
  • Umehara, K. I., Iwatsubo, T., Noguchi, K., Usui, T., Kamimura, H. (2008). Effect of cationic drugs on the transporting activity of human and rat OCT/Oct 1-3 in vitro and implications for drug-drug interactions. Xenobiotica 38:1203–1218.
  • van Giersbergen, P. L., Halabi, A., Dingemanse, J. (2002). Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 53:589–595.
  • Vavricka, S. R., Van Montfoort, J., Ha, H. R., Meier, P. J., Fattinger, K. (2002). Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36:164–172.
  • Vormfelde, S. V., Toliat, M. R., Schirmer, M., Meineke, I., Nurnberg, P., Brockmoller, J. (2008). The polymorphisms Asn130Asp and Val174Ala in OATP1B1 and the CYP2C9 allele *3 independently affect torsemide pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 83:815–817.
  • Wang, J. S., Neuvonen, M., Wen, X., Backman, J. T., Neuvonen, P. J. (2002). Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 30:1352–1356.
  • Wang, L., Giannoudis, A., Lane, S., Williamson, P., Pirmohamed, M., Clark, R. E. (2008). Expression of the uptake drug transporter, hOCT1, is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 83:258–264.
  • Werner, U., Werner, D., Heinbüchner, S., Graf, B., Ince, H., Kische, S., et al. (2009). Gender is an improtant determinant of the disposition of the loop diuretic torasemide. J Clin Pharmacol (In press).
  • Wu, X., Prasad, P. D., Leibach, F. H., Ganapathy, V. (1998). cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun 246:589–595.
  • Xiang, X., Jada, S.R., Li, H.H., Fan, L., Tham, L.S., Wong, C.I., Lee, S.C., et al.(2006). Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics 16(9):683–91.
  • Xiang, X., Han, Y., Neuvonen, M., Pasanen, M. K., Kalliokoski, A., Backman, J. T., et al. (2009). Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans. Pharmacogenet Genom 19:447–457.
  • 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.
  • 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.
  • Zhang, L., Schaner, M. E., Giacomini, K. M. (1998). Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther 286:354–361.
  • Zhang, W., He, Y. J., Han, C. T., Liu, Z. Q., Li, Q., Fan, L., et al. (2006). Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide. Br J Clin Pharmacol 62:567–572.
  • Zhou, S., Yung Chan, S. Cher, Goh, B., Chan, E., Duan, W., Huang, M. et, al. (2005). Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet 44:279–304.

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