Abstract
Recently, hepatic transport processes have been recognized as important determinants of drug disposition. Therefore, it is not surprising that characterization of the hepatic transport and biliary excretion properties of potential drug candidates is an important part of the drug development process. Such information also is useful in understanding alterations in the hepatobiliary disposition of compounds due to drug interactions or disease states. Basolateral transport systems are responsible for translocating molecules across the sinusoidal membrane, whereas active canalicular transport systems are responsible for the biliary excretion of drugs and metabolites. Several transport proteins involved in basolateral transport have been identified including the Na+-taurocholate co-transporting polypeptide [NTCP (SLC10A1)], organic anion transporting polypeptides [OATPs (SLCO family)], multidrug resistance-associated proteins [MRPs (ABCC family)], and organic anion and cation transporters [OATs, OCTs (SLC22A family)]. Canalicular transport is mediated predominantly via P-glycoprotein (ABCB1), MRP2 (ABCC2), the bile salt export pump [BSEP (ABCB11)], and the breast cancer resistance protein [BCRP (ABCG2)]. This review summarizes current knowledge regarding these hepatic basolateral and apical transport proteins in terms of substrate specificity, regulation by nuclear hormone receptors and intracellular signaling pathways, genetic differences, and role in drug interactions. Transport knockout models and other systems available for hepatobiliary transport studies also are discussed. This overview of hepatobiliary drug transport summarizes knowledge to date in this rapidly growing field and emphasizes the importance of understanding these fundamental processes in hepatic drug disposition.
REFERENCES
B. Hagenbuch and P. J. Meier. 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 (2004).
B. Hagenbuch, B. Stieger, M. Foguet, H. Lubbert, and P. J. Meier. Functional expression cloning and characterization of the hepatocyte Na/bile acid cotransport system. Proc. Natl. Acad. Sci. USA 88:10629-10633 (1991).
P. J. Meier, U. Eckhardt, A. Schroeder, B. Hagenbuch, and B. Stieger. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology 26: 1667-1677 (1997).
G. Kullak-Ublick, M. G. Ismair, R. Kubitz, M. Schmitt, D. Haussinger, B. Stieger, B. Hagenbuch, P. J. Meier, U. Beuers, and G. Paumgartner. Stable expression and functional characterization of a Na+-taurocholate cotransporting green fluorescent protein in human hepatoblastoma HepG2 cells. Cytotechnology34:1-9 (2000).
E. C. Friesema, R. Docter, E. P. Moerings, B. Stieger, B. Hagenbuch, P. J. Meier, E. P. Krenning, G. Hennemann, and T. J. Visser. Identification of thyroid hormone transporters. Biochem. Biophys. Res. Commun. 254:497-501 (1999).
L. Li, T. K. Lee, P. J. Meier, and N. Ballatori. Identification of glutathione as a driving force and leukotriene C4 as a substrate for Oatp1, the hepatic sinusoidal organic solute transporter. J. Biol. Chem. 273:16184-16191 (1998).
G. A. Kullak-Ublick, M. G. Ismair, B. Stieger, L. Landmann, R. Huber, F. Pizzagalli, K. Fattinger, P. J. Meier, and B. Hagenbuch. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525-533 (2001).
I. Tamai, J. Nezu, H. Uchino, Y. Sai, A. Oku, M. Shimane, and A. Tsuji. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun. 273:251-260 (2000).
G. A. Kullak-Ublick, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatology 20: 411-416 (1994).
V. Cattori, J. E. van Montfoort, B. Stieger, L. Landmann, D. K. Meijer, K. H. Winterhalter, P. J. Meier, and B. Hagenbuch. Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch. 443:188-195 (2001).
K. Fujiwara, H. Adachi, T. Nishio, M. Unno, T. Tokui, M. Okabe, T. Onogawa, T. Suzuki, N. Asano, M. Tanemoto, M. Seki, K. Shiiba, M. Suzuki, Y. Kondo, K. Nunoki, T. Shimosegawa, K. Iinuma, S. Ito, S. Matsuno, and T. Abe. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology 142: 2005-2012 (2001).
R. G. Tirona and R. B. Kim. Pharmacogenomics of organic anion-transporting polypeptides (OATP). Adv. Drug Deliv. Rev. 54:1343-1352 (2002).
T. Sekine, S. H. Cha, M. Tsuda, N. Apiwattanakul, N. Nakajima, Y. Kanai, and H. Endou. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 429:179-182 (1998).
H. Kusuhara, T. Sekine, and N. Utusnomiya-Tate. Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J. Biol. Chem. 274:13675-13680 (1999).
G. A. Kullak-Ublick, U. Beuers, and G. Paumgartner. Hepatobiliary transport. J. Hepatol. 32:3-18 (2000).
W. Sun, R. R. Wu, P. D. van Poelje, and M. D. Erion. Isolation of a family of organic anion transporters from human liver and kidney. Biochem. Biophys. Res. Commun. 283:417-422 (2001).
A. Enomoto, M. Takeda, M. Shimoda, S. Narikawa, Y. Kobayashi, T. Yamamoto, T. Sekine, S. H. Cha, T. Niwa, and H. Endou. Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J. Pharmacol. Exp. Ther. 301: 797-802 (2002).
H. Kimura, M. Takeda, S. Narikawa, A. Enomoto, K. Ichida, and H. Endou. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J. Pharmacol. Exp. Ther. 301:293-298 (2002).
E. Babu, M. Takeda, S. Narikawa, Y. Kobayashi, T. Yamamoto, S. H. Cha, T. Sekine, D. Sakthisekaran, and H. Endou. Human organic anion transporters mediate the transport of tetracycline. Jpn. J. Pharmacol. 88:69-76 (2002).
S. Khamdang, M. Takeda, R. Noshiro, S. Narikawa, A. Enomoto, N. Anzai, P. Piyachaturawat, and H. Endou. Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs. J. Pharmacol. Exp. Ther. 303:534-539 (2002).
M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, Y. Kobayashi, T. Yamamoto, S. H. Cha, T. Sekine, and H. Endou. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J. Pharmacol. Exp. Ther. 300:918-924 (2002).
M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, M. Hosoyamada, S. H. Cha, T. Sekine, and H. Endou. Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J. Pharmacol. Exp. Ther. 302:666-671 (2002).
E. Babu, M. Takeda, S. Narikawa, Y. Kobayashi, A. Enomoto, A. Tojo, S. H. Cha, T. Sekine, D. Sakthisekaran, and H. Endou. Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim. Biophys. Acta 1590:64-75 (2002).
D. Grundemann, V. Gorboulev, S. Gambaryan, M. Veyhl, and H. Koepsell. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549-552 (1994).
L. Zhang, M. J. Dresser, A. T. Gray, S. C. Yost, S. Terashita, and K. M. Giacomini. Cloning and functional expression of a human liver organic cation transporter. Mol. Pharmacol. 51:913-921 (1997).
F. Meyer-Wentrup, U. Karbach, V. Gorboulev, P. Arndt, and H. Koepsell. Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem. Biophys. Res. Commun.248:673-678 (1998).
M. Hayer-Zillgen, M. Brüss, and H. Bönisch. Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br. J. Pharmacol. 136:829-836 (2002).
I. Tamai, H. Yabuuchi, J. Nezu, Y. Sai, A. Oku, M. Shimane, and A. Tsuji. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett. 419:107-111 (1997).
X. Wu, P. D. Prasad, F. H. Leibach, and V. Ganapathy. 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 (1998).
P. Borst, R. Evers, and M. Kool, J. Wijnholds, The multidrug resistance protein family. Biochim. Biophys. Acta 146:347-357 (1999).
H. Roelofsen, M. Muller, and P. L. Jansen. Regulation of organic anion transport in the liver. Yale J. Biol. Med. 70:435-445 (1997).
M. J. Flens, G. J. Zaman, P. van der Valk, M. A. Izquierdo, A. B. Schroeijers, G. L. Scheffer, P. van der Groep, M. de Haas, C. J. Meijer, and R. J. Scheper. Tissue distribution of the multidrug resistance protein. Am. J. Pathol. 148:1237-1247 (1996).
D. W. Loe, R. G. Deeley, and S. P. Cole. Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res. 58:5130-5136 (1998).
T. Hirohashi, H. Suzuki, and Y. Sugiyama. Characterization of the transport properties of cloned rat multidrug resistanceassociated protein 3 (MRP3). J. Biol. Chem. 274:15181-15185 (1999).
T. Hirohashi, H. Suzuki, H. Takikawa, and Y. Sugiyama. ATPdependent transport of bile salts by rat multidrug resistanceassociated protein 3 (Mrp3). J. Biol. Chem. 275:2905-2910 (2000).
H. Xiong, K. C. Turner, E. S. Ward, P. L. Jansen, and K. L. Brouwer. Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR-rats. J. Pharmacol. Exp. Ther. 295:512-518 (2000).
K. Ogawa, H. Suzuki, T. Hirohashi, T. Ishikawa, P. J. Meier, K. Hirose, T. Akizawa, M. Yoshioka, and Y. Sugiyama. Characterization of inducible nature of MRP3 in rat liver. Am. J. Physiol. 278:G438-G446 (2000).
J. Konig, D. Rost, Y. Cui, and D. Keppler. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 29:1156-1163 (1999).
G. Reid, P. Wielinga, N. Zelcer, M. De Haas, L. Van Deemter, J. Wijnholds, J. Balzarini, and P. Borst. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol. Pharmacol. 63:1094-1103 (2003).
Z. S. Chen, K. Lee, and G. D. Kruh. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J. Biol. Chem. 276:33747-33754 (2001).
G. Jedlitschky, B. Burchell, and D. Keppler. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J. Biol. Chem. 275:30069-30074 (2000).
Z. S. Chen, K. Lee, S. Walther, R. B. Raftogianis, M. Kuwano, H. Zeng, and G. D. Kruh. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 62:3144-3150 (2002).
J. D. Schuetz, M. C. Connelly, D. Sun, S. G. Paibir, P. M. Flynn, R. V. Srinivas, A. Kumar, and A. Fridland. MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat. Med. 5:1048-1051 (1999).
N. Zelcer, G. Reid, P. Wielinga, A. Kuil, I. van der Heijden, J. D. Schuetz, and P. Borst. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem. J. 371:361-367 (2003).
E. G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R. B. Kim, V. Ramachandran, B. J. Komoroski, R. Venkataramanan, H. Cai, C. J. Sinal, F. J. Gonzalez, and J. D. Schuetz. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J. Biol. Chem. 276:39411-39418 (2001).
J. Madon, B. Hagenbuch, L. Landmann, P. J. Meier, and B. Stieger. Transport function and hepatocellular localization of mrp6 in rat liver. Mol. Pharmacol. 57:634-641 (2000).
M. Kool, M. van der Linden, M. de Haas, F. Baas, and P. Borst. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res. 59:175-182 (1999).
E. Hopper, M. G. Belinsky, H. Zeng, A. Tosolini, J. R. Testa, and G. D. Kruh. Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily. Cancer Lett. 162:181-191 (2001).
Z. S. Chen, E. Hopper-Borge, M. G. Belinsky, I. Shchaveleva, E. Kotova, and G. D. Kruh. Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol. Pharmacol. 63:351-358 (2003).
T. K. Bera, S. Lee, G. Salvatore, B. Lee, and I. Pastan. MRP8, a new member of ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer. Mol. Med. 7:509-516 (2001).
Y. Guo, E. Kotova, Z. S. Chen, K. Lee, E. Hopper-Borge, M. G. Belinsky, and G. D. Kruh. MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2_,3_-dideoxycytidine and 9_-(2_-phosphonylmethoxyethyl)adenine. J. Biol. Chem. 278:29509-29514 (2003).
S. C. Hyde, P. Emsley, M. J. Hartshorn, M. M. Mimmack, U. Gileadi, S. R. Pearce, M. P. Gallagher, D. R. Gill, R. E. Hubbard, and C. F. Higgins. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature 346:362-365 (1990).
T. Gerloff, B. Stieger, B. Hagenbuch, J. Madon, L. Landmann, J. Roth, A. F. Hofmann, and P. J. Meier. The sister of Pglycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273:10046-10050 (1998).
S. S. Strautnieks, L. N. Bull, A. S. Knisely, S. A. Kocoshis, N. Dahl, H. Arnell, E. Sokal, K. Dahan, S. Childs, V. Ling, M. S. Tanner, A. F. Kagalwalla, A. Nemeth, J. Pawlowska, A. Baker, G. Mieli-Vergani, N. B. Freimer, R. M. Gardiner, and R. J. Thompson. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20:233-238 (1998).
P. L. Jansen, S. S. Strautnieks, E. Jacquemin, M. Hadchouel, E. M. Sokal, G. J. Hooiveld, J. H. Koning, A. De Jager-Krikken, F. Kuipers, F. Stellaard, C. M. Bijleveld, A. Gouw, H. Van Goor, R. J. Thompson, and M. Muller. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 117:1370-1379 (1999).
J. Konig, A. T. Nies, Y. Cui, I. Leier, and D. Keppler. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta 1461:377-394 (1999).
P. L. M. Jansen, G. M. Groothuis, W. H. Peters, and D. K. F. Meijer. Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditaryconjugated hyperbilirubinemia. Hepatology 7:71-76 (1987).
C. C. Paulusma, P. J. Bosma, G. J. R. Zaman, C. T. M. Bakker, M. Otter, G. L. Scheffer, R. J. Scheper, P. Borst, and R. P. J. Oude Elferink. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271:1126-1128 (1996).
Y. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama. Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am. J. Pathol. 272:G16-G22 (1997).
T. Hirohashi, H. Suzuki, K. Ito, K. Ogawa, K. Kume, T. Shimizu, and Y. Sugiyama. Hepatic expression of multidrug resistanceassociated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol. Pharmacol. 53:1068-1075 (1998).
I. Pastan and M. Gottesman. Multiple-drug resistance in human cancer. N. Engl. J. Med. 316:1388-1393 (1987).
R. P. J. Oude Elferink, D. K. F. Meijer, F. Kuipers, P. L. M. Jansen, A. K. Groen, and G. M. M. Groothuis. Hepatobiliary secretion of organic compounds: molecular mechanisms of membrane transport. Biochim. Biophys. Acta 1241:215-268 (1995).
D. Schmid, G. Ecker, S. Kopp, M. Hitzler, and P. Chiba. Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem. Pharmacol. 58:1447-1456 (1999).
J. W. Smit, A. H. Schinkel, M. Muller, B. Weert, and D. K. Meijer. Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdr1a gene disruption. Hepatology 27:1056-1063 (1998).
J. W. Smit, B. Weert, A. H. Schinkel, and D. K. Meijer. Heterologous expression of various P-glycoproteins in polarized epithelial cells induces directional transport of small (type 1) and bulky (type 2) cationic drugs. J. Pharmacol. Exp. Ther. 286:321-327 (1998).
C. J. Matheny, M. W. Lamb, K. L. R. Brouwer, and G. M. Pollack. Pharmacokinetic and pharmacodynamic implications of Pglycoprotein modulation. Pharmacotherapy 21:778-796 (2001).
S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L. B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Application of threedimensional quantitative structure-activity relationships of Pglycoprotein inhibitors and substrates. Mol. Pharmacol. 61:974-981 (2002).
S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L. B. Lan, K. Yasuda, R. L. Shepard, M. A. Winter, J. D. Schuetz, J. H. Wikel, and S. A. Wrighton. Three-dimensional quantitative structure-activity relationships of inhibitors of Pglycoprotein. Mol. Pharmacol. 61:964-973 (2002).
T. R. Stouch and O. Gudmundsson. Progress in understanding the structure-activity relationships of P-glycoprotein. Adv. Drug Deliv. Rev. 54:315-328 (2002).
Y. M. Lee, I. S. Song, S. G. Kim, M. G. Lee, S. J. Chung, and C. K. Shim. The suppressed expression and functional activity of hepatic P-glycoprotein in rats with protein-calorie malnutrition. J. Pharm. Sci. 92:1323-1330 (2003).
V. A. Patel, M. J. Dunn, and A. Sorokin. Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. J. Biol. Chem. 277:38915-38920 (2002).
M. Sukhai and M. Piquette-Miller. Regulation of the multidrug resistance genes by stress signals. J. Pharm. Sci. 3:268-280 (2000).
M. P. McRae, K. L. Brouwer, and A. D. Kashuba. Cytokine regulation of P-glycoprotein. Drug Metab. Rev. 35:19-33 (2003).
P. P. Annaert, R. Z. Turncliff, C. L. Booth, D. R. Thakker, and K. L. Brouwer. P-glycoprotein-mediated in vitro biliary excretion in sandwich-cultured rat hepatocytes. Drug Metab. Dispos. 29:1277-1283 (2001).
A. J. Smith, A. van Helvoort, G. van Meer, K. Szabo, E. Welker, G. Szakacs, A. Varadi, B. Sarkadi, and P. Borst. MDR3 Pglycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem. 275: 23530-23539 (2000).
L. A. Doyle, W. Yang, L. V. Abruzzo, T. Krogmann, Y. Gao, A. K. Rishi, and D. D. Ross. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA 95:15665-15670 (1998).
M. Suzuki, H. Suzuki, Y. Sugimoto, and Y. Sugiyama. ABCG2 transports sulfated conjugates of steroids and xenobiotics. J. Biol. Chem. 278:22644-22649 (2003).
M. Maliepaard, G. L. Scheffer, I. F. Faneyte, M. A. van Gastelen, A. C. L. M. Pijnenborg, A. H. Schinkel, M. J. van De Vijver, R. J. Scheper, and J. H. M. Schellens. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61:3458-3464 (2001).
D. Houssin, M. Capron, C. Celier, T. Cresteil, F. Demaugre, and P. Beaune. Evaluation of isolated human hepatocytes. Life Sci.33:1805-1809 (1983).
L. B. Tee, T. Seddon, A. R. Boobis, and D. S. Davies. Drug metabolising activity of freshly isolated human hepatocytes. Br. J. Clin. Pharmacol. 19:279-294 (1985).
G. M. Groothuis, C. E. Hulstaert, D. Kalicharan, and M. J. Hardonk. Plasma membrane specialization and intracellular polarity of freshly isolated rat hepatocytes. Eur. J. Cell Biol. 26: 43-51 (1981).
G. Ihrke, E. B. Neufeld, T. Meads, M. R. Shanks, D. Cassio, M. Laurent, T. A. Schroer, R. E. Pagano, and A. L. Hubbard. WIF-B cells: an in vitro model for studies of hepatocyte polarity. J. Cell Biol. 123:1761-1775 (1993).
Y. Sai, A. T. Nies, and I. M. Arias. Bile acid secretion and direct targeting of mdr1-green fluorescent protein from golgi to the canalicular membrane in polarized WIF-B cells. J. Cell Sci. 112: 4535-4545 (1999).
M. M. Zegers and D. Hoekstra. Mechanisms and functional features of polarized membrane traffic in epithelial and hepatic cells. Biochem. J. 336:257-269 (1998).
J. A. Dranoff, M. McClure, A. D. Burgstahler, L. A. Denson, A. R. Crawford, J. M. Crawford, S. J. Karpen, and M. H. Nathanson. Short-term regulation of bile acid uptake by microfilament-dependent translocation of rat ntcp to the plasma membrane. Hepatology 30:223-229 (1999).
J. H. Fentem, B. Foster, C. O. Mills, R. Coleman, and J. K. Chipman. Biliary excretion of fluorescent cholephiles in hepatocyte couplets: an in vitro model for hepatobiliary and hepatotoxicity studies. Toxicol. in Vitro 4:452-457 (1990).
J. Graf and J. L. Boyer. The use of isolated rat hepatocyte couplets in hepatobiliary physiology. J. Hepatol. 10:387-394 (1990).
C. O. Mills, P. Milkiewicz, M. Muller, M. G. Roma, R. Havinga, R. Coleman, F. Kuipers, P. L. Jansen, and E. Elias. Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids: a study in isolated hepatocyte couplets and TR-rats. J. Hepatol. 31:678-684 (1999).
G. M. Groothuis and D. K. Meijer. Drug traffic in the hepatobiliary system. J. Hepatol. 24:3-28 (1996).
E. L. LeCluyse, P. L. Bullock, and A. Parkinson. Strategies for restoration and maintenance of normal hepatic structure and function in long-term cultures of rat hepatocytes. Adv. Drug Deliv. Rev. 22:133-186 (1996).
X. Liu, E. L. LeCluyse, K. R. Brouwer, R. M. Lightfoot, J. I. Lee, and K. L. Brouwer. Use of Ca2+ modulation to evaluate biliary excretion in sandwich-cultured rat hepatocytes. J. Pharmacol. Exp. Ther. 289:1592-1599 (1999).
X. Liu, J. P. Chism, E. L. LeCluyse, K. R. Brouwer, and K. L. Brouwer. Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab. Dispos. 27:637-644 (1999).
X. Liu, E. L. LeCluyse, K. R. Brouwer, L. S. Gan, J. J. Lemasters, B. Stieger, P. J. Meier, and K. L. Brouwer. Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am. J. Physiol. 277:G12-G21 (1999).
B. L. Blitzer and C. B. Donovan. A new method for the rapid isolation of basolateral plasma membrane vesicles from rat liver. Characterization, validation, and bile acid transport studies. J. Biol. Chem. 259:9295-9301 (1984).
P. J. Meier, A. St Meier-Abt, C. Barrett, and J. L. Boyer. Mechanisms of taurocholate transport in canalicular and basolateral rat liver plasma membrane vesicles. Evidence for an electrogenic canalicular organic anion carrier. J. Biol. Chem. 259: 10614-10622 (1984).
D. A. Novak, F. C. Ryckman, and F. J. Suchy. Taurocholate transport by basolateral plasma membrane vesicles isolated from human liver. Hepatology 10:447-453 (1989).
H. Wolters, M. Spiering, A. Gerding, M. J. Slooff, F. Kuipers, M. J. Hardonk, and R. J. Vonk. Isolation and characterization of canalicular and basolateral plasma membrane fractions from human liver. Biochim. Biophys. Acta 1069:61-69 (1991).
H. Ishizuka, K. Konno, T. Shiina, H. Naganuma, K. Nishimura, K. Ito, H. Suzuki, and Y. Sugiyama. Species differences in the transport activity for organic anions across the bile canalicular membrane. J. Pharmacol. Exp. Ther. 290:1324-1330 (1999).
M. Sasaki, H. Suzuki, K. Ito, T. Abe, and Y. Sugiyama. Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/ SLC21A6) and Multidrug resistance-associated protein 2 (MRP2/ABCC2). J. Biol. Chem. 277:6497-6503 (2002).
Y. Cui, J. Konig, and D. Keppler. Vectorial transport by doubletransfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol. Pharmacol. 60:934-943 (2001).
Y. Cui, J. Konig, J. K. Buchholz, H. Spring, I. Leier, and D. Keppler. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. 55:929-937 (1999).
X. Tian, P. Zhang, and K. L. Brouwer. Modulation of multidrug resistance-associated proteins 2 and 3 expression and function with small interfering RNA in sandwich-cultured rat hepatocytes. Mol. Pharmacol. (2004, in review).
M. Muller. Transcriptional control of hepatocanalicular transporter gene expression. Semin. Liver Dis. 20:323-337 (2000).
L. A. Denson, E. Sturm, W. Echevarria, T. L. Zimmerman, M. Makishima, D. J. Mangelsdorf, and S. J. Karpen. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140-147 (2001).
L. A. Denson, K. L. Auld, D. S. Schiek, M. H. McClure, D. J. Mangelsdorf, and S. J. Karpen. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation. J. Biol. Chem. 275:8835-8843 (2000).
D. Jung, M. Podvinec, U. A. Meyer, D. J. Mangelsdorf, M. Fried, P. J. Meier, and G. A. Kullak-Ublick. Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122:1954-1966 (2002).
J. L. Staudinger, A. Madan, K. M. Carol, and A. Parkinson. Regulation of drug transporter gene expression by nuclear receptors. Drug Metab. Dispos. 31:523-527 (2003).
H. Xiong, K. Yoshinari, K. L. Brouwer, and M. Negishi. Role of constitutive androstane receptor in the in vivo induction of Mrp3 and CYP2B1/2 by phenobarbital. Drug Metab. Dispos. 30:918-923 (2002).
M. Ananthanarayanan, N. Balasubramanian, M. Makishima, D. J. Mangelsdorf, and F. J. Suchy. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem. 276:28857-28865 (2001).
H. M. Kauffmann, S. Pfannschmidt, H. Zöller, A. Benz, B. Vorderstemann, J. I. Webster, and D. Schrenk. Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression. Toxicology 171:137-146 (2002).
H. R. Kast, B. Goodwin, P. T. Tarr, S. A. Jones, A. M. Anisfeld, C. M. Stoltz, P. Tontonoz, S. Kliewer, T. M. Willson, and P. A. Edwards. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J. Biol. Chem. 277:2908-2915 (2002).
S. A. Kliewer, J. T. Moore, L. Wade, J. L. Staudinger, M. A. Watson, S. A. Jones, D. D. McKee, B. B. Oliver, T. M. Willson, R. H. Zetterstrom, T. Perlmann, and J. M. Lehmann. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73-82 (1998).
A. Geick, M. Eichelbaum, and O. Burk. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276:14581-14587 (2001).
T. W. Synold, I. Dussault, and B. M. Forman. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat. Med. 7:584-590 (2001).
T. Kok, V. W. Bloks, H. Wolters, R. Havinga, P. L. Jansen, B. Staels, and F. Kuipers. Peroxisome proliferator-activated receptor _ (PPAR_)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem. J. 369:539-547 (2003).
G. A. Kullak-Ublick and M. B. Becker. Regulation of drug and bile salt transporters in liver and intestine. Drug Metab. Rev. 35:305-317 (2003).
J. L. Boyer and C. J. Soroka. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets. Gastroenterology 109:1600-1611 (1995).
S. Mukhopadhayay, M. Ananthanarayanan, B. Stieger, P. J. Meier, F. J. Suchy, and M. S. Anwer. cAMP increases liver Na+-taurocholate cotransport by translocation transporter to plasma membranes. Am. J. Physiol. 273:G842-G848 (1997).
H. Kipp and I. M. Arias. Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters. Semin. Liver Dis. 20:339-351 (2000).
A. M. Durand-Schneider, C. T. M. Bakker, H. Roelofsen, E. Middelkoop, R. Ottenhoff, M. Heijn, and P. L. M. Jansen. Microtubule disruption interferes with the structural and functional integrity of the apical pole in primary cultures of rat hepatocytes. Eur. J. Cell Biol. 56:260-268 (1991).
R. P. J. Oude Elferink, C. T. M. Bakker, H. Roelofsen, E. Middelkoop, R. Ottenhoff, M. Heijn, and P. L. M. Jansen. Accumulation of organic anion in intracellular vesicles of cultured rat hepatocytes is mediated by the canalicular multispecific organic anion transporter. Hepatology 17:434-444 (1993).
H. Roelofsen, C. J. Soroka, D. Keppler, and J. L. Boyer. Cyclic AMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMoat) to the apical domain in hepatocyte couplets. J. Cell Sci. 111:1137-1145 (1998).
R. Kubitz, D. D'Urso, D. Keppler, and D. Haussinger. Osmodependent dynamic localization of the multidrug resistance protein 2 in the rat hepatocyte canalicular membrane. Gastroenterology 113:1438-1442 (1997).
Z. Gatmaitan, A. T. Nies, and I. M. Arias. Regulation and translocation of ATP-dependent apical membrane proteins in rat liver. Am. J. Pathol. 35:G1041-G1049 (1997).
J. S. Glavy, S. M. Wu, P. J. Wang, G. A. Orr, and A. W. Wolkoff. Down-regulation by extracellular ATP of rat hepatocyte organic anion transport is mediated by serine phosphorylation of oatp1. J. Biol. Chem. 275:1479-1484 (2000).
Y. Shitara, T. Itoh, H. Sato, A. P. Li, and Y. Sugiyama. 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 (2003).
W. Muck, I. Mai, L. Fritsche, K. Ochmann, G. Rohde, S. Unger, A. Johne, S. Bauer, K. Budde, I. Roots, and H. H. Neumayer. and J. Kuhlmann. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin. Pharmacol. Ther. 65:251-261 (1999).
B. Angelin, A. Arvidsson, R. Dahlqvist, A. Hedman, and K. Schenck-Gustafsson. Quinidine reduces biliary clearance of digoxin in man. Eur. J. Clin. Invest. 17:262-265 (1987).
M. Horio, M. M. Gottesman, and I. Pastan. ATP-dependent transport of vinblastine in vesicles from human multidrugresistant cells. Proc. Natl. Acad. Sci. USA 85:3580-3584 (1988).
C. L. Booth, K. R. Brouwer, and K. L. Brouwer. Effect of multidrug resistance modulators on the hepatobiliary disposition of doxorubicin in the isolated perfused rat liver. Cancer Res. 58: 3641-3648 (1998).
J. van Asperen, O. van Tellingen, and J. H. Beijnen. The role of mdr1a P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metab. Dispos. 28: 264-267 (2000).
J. Riley, J. Styles, R. D. Verschoyle, L. A. Stanley, I. N. White, and T. W. Gant. Association of tamoxifen biliary excretion rate with prior tamoxifen exposure and increased mdr1b expression. Biochem. Pharmacol. 60:233-239 (2000).
K. Fattinger, C. Funk, M. Pantze, C. Weber, J. Reichen, B. Stieger, and P. J. Meier. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69: 223-231 (2001).
V. J. Wacher, C. Y. Wu, and L. Z. Benet. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog. 13:129-134 (1995).
L. Huang, S. A. Wring, J. L. Woolley, K. R. Brouwer, C. Serabjit-Singh, and J. W. Polli. Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors. Drug Metab. Dispos. 29:754-760 (2001).
E. G. Schuetz, W. T. Beck, and J. D. Schuetz. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol. Pharmacol. 49:311-318 (1996).
E. G. Schuetz, A. H. Schinkel, M. V. Relling, and J. D. Schuetz. P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc. Natl. Acad. Sci. USA 93:4001-4005 (1996).
L. Salphati and L. Z. Benet. Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem. Pharmacol. 55:387-395 (1998).
K. Yasuda, L. B. Lan, D. Sanglard, K. Furuya, J. D. Schuetz, and E. G. Schuetz. Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J. Pharmacol. Exp. Ther. 303:323-332 (2002).
C. Y. Wu and L. Z. Benet. Disposition of tacrolimus in isolated perfused rat liver: influence of troleandomycin, cyclosporine, and gg918. Drug Metab. Dispos. 31:1292-1295 (2003).
E. G. Schuetz, D. R. Umbenhauer, K. Yasuda, C. Brimer, L. Nguyen, M. V. Relling, J. D. Schuetz, and A. H. Schinkel. Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes. Mol. Pharmacol. 57:188-197 (2000).
L. B. Lan, J. T. Dalton, and E. G. Schuetz. Mdr1 limits CYP3A metabolism in vivo. Mol. Pharmacol. 58:863-869 (2000).
J. M. Lehmann, D. D. McKee, M. A. Watson, T. M. Willson, J. T. Moore, and S. A. Kliewer. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102: 1016-1023 (1998).
A. Iida, S. Saito, A. Sekine, C. Mishima, K. Kondo, Y. Kitamura, S. Harigae, S. Osawa, and Y. Nakamura. Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic aniontransporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J. Hum. Genet. 46:668-683 (2001).
T. Nozawa, M. Nakajima, I. Tamai, K. Noda, J. Nezu, Y. Sai, A. Tsuji, and T. Yokoi. 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 (2002).
C. Michalski, Y. Cui, A. T. Nies, A. K. Nuessler, P. Neuhaus, U. M. Zanger, K. Klein, M. Eichelbaum, D. Keppler, and J. Konig. A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J. Biol. Chem. 277:43058-43063 (2002).
R. G. Tirona, B. F. Leake, G. Merino, and R. B. Kim. 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 (2001).
Y. Nishizato, I. Ieiri, H. Suzuki, M. Kimura, K. Kawabata, T. Hirota, H. Takane, S. Irie, H. Kusuhara, Y. Urasaki, A. Urae, S. Higuchi, K. Otsubo, and Y. Sugiyama. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73:554-565 (2003).
S. Conrad, H. M. Kauffmann, K. Ito, E. M. Leslie, R. G. Deeley, D. Schrenk, and S. P. C. Cole. A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance. Pharmacogenetics 12: 321-330 (2002).
S. Ito, I. Ieiri, M. Tanabe, A. Suzuki, S. Higuchi, and K. Otsubo. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 11:175-184 (2001).
D. P. Germain, V. Remones, J. Perdu, and X. Jeunemaitre. Identification of two polymorphisms (c189G>C; c190T>C) in exon 2 of the human MRP6 gene (ABCC6) by screening of Pseudoxanthoma elasticum patients: possible sequence correction? Hum. Mutat. 16:449 (2000).
I. N. Dubin and F. B. Johnson. Chronic idiopathic jaundice with unidentified pigment in liver cells. Medicine (Baltimore) 33:155-179 (1954).
J. Kartenbeck, U. Leuschner, R. Mayer, and D. Keppler. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061-1066 (1996).
M. Wada, S. Toh, K. Taniguchi, T. Nakamura, T. Uchiumi, K. Kohno, I. Yoshida, A. Kimura, S. Sakisaka, Y. Adachi, and M. Kuwano. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum. Mol. Genet. 7:203-207 (1998).
V. Keitel, J. Kartenbeck, A. T. Nies, H. Spring, M. Brom, and D. Keppler. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology 32: 1317-1328 (2000).
K. Hashimoto, T. Uchiumi, T. Konno, T. Ebihara, T. Nakamura, M. Wada, S. Sakisaka, F. Maniwa, T. Amachi, K. Ueda, and M. Kuwano. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology 36:1236-1245 (2002).
M. Schwab, M. Eichelbaum, and M. F. Fromm. Genetic polymorphisms of the human MDR1 drug transporter. Annu. Rev. Pharmacol. Toxicol. 43:285-307 (2003).
M. F. Fromm. The influence of MDR1 polymorphisms on Pglycoprotein expression and function in humans. Adv. Drug Deliv. Rev. 54:1295-1310 (2002).
A. Sparreboom, R. Danesi, Y. Ando, J. Chan, and W. D. Figg. Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resist. Updat 6:71-84 (2003).
S. Hoffmeyer, O. Burk, O. von Richter, H. P. Arnold, J. Brockmoller, A. Johne, I. Cascorbi, T. Gerloff, I. Roots, M. Eichelbaum, and U. Brinkmann. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 97:3473-3478 (2000).
T. Sakaeda, T. Nakamura, M. Horinouchi, M. Kakumoto, N. Ohmoto, T. Sakai, Y. Morita, T. Tamura, N. Aoyama, M. Hirai, M. Kasuga, and K. Okumura. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm. Res. 18:1400-1404 (2001).
K. Tang, S. M. Ngoi, P. C. Gwee, J. M. Z. Chua, E. J. D. Lee, S. S. Chong, and C. G. L. Lee. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 12:437-450 (2002).
C. Kimchi-Sarfaty, J. J. Gribar, and M. M. Gottesman. Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol. Pharmacol. 62:1-6 (2002).
H. Mitomo, R. Kato, A. Ito, S. Kasamatsu, Y. Ikegami, I. Kii, A. Kudo, E. Kobatake, Y. Sumino, and T. Ishikawa. A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem. J. 373:767-774 (2003).
A. H. Schinkel, J. J. Smit, O. van Tellingen, J. H. Beijnen, E. Wagenaar, L. van Deemter, C. A. Mol, M. A. van der Valk, E. C. Robanus-Maandag, H. P. te Riele, A. J. M. Berns, and P. Borst. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491-502 (1994).
M. Nadai, T. Hasegawa, L. Wang, O. Tagaya, and T. Nabeshima. Alterations in the pharmacokinetics and protein binding of enprofylline in Eisai hyperbilirubinemic rats. Drug Metab. Dispos. 22:561-565 (1994).
J. Wijnholds, C. A. Mol, G. L. Scheffer, R. J. Scheper, and P. Borst. Multidrug resistance protein 5, a candidate multispecific organic anion transporter. Proc. Am. Assoc. Cancer Res. 40:315 (1999).
J. Wijnholds, R. Evers, M. R. van Leusden, C. A. Mol, G. J. Zaman, U. Mayer, J. H. Beijnen, M. van der Valk, P. Krimpen-fort, and P. Borst. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat. Med. 3:1275-1279 (1997).
A. Lorico, G. Rappa, R. A. Finch, D. Yang, R. A. Flavell, and A. C. Sartorelli. Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res. 57: 5238-5242 (1997).
M. Cvetkovic, B. Leake, M. F. Fromm, G. R. Wilkinson, and R. B. Kim. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab. Dispos. 27:866-871 (1999).
Y. Cui, J. Konig, I. Leier, U. Buchholz, and D. Keppler. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J. Biol. Chem. 276:9626-9630 (2001).
T. Abe, M. Kakyo, T. Tokui, R. Nakagomi, T. Nishio, D. Nakai, H. Nomura, M. Unno, M. Suzuki, T. Naitoh, S. Matsuno, and H. Yawo. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. 274:17159-17163 (1999).
D. Nakai, R. Nakagomi, Y. Furuta, T. Tokui, T. Abe, T. Ikeda, and K. Nishimura. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 297:861-867 (2001).
S. R. Vavricka, J. Van Montfoort, H. R. Ha, P. J. Meier, and K. Fattinger. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36:164-172 (2002).
H. Hasannejad, M. Takeda, K. Taki, S. H. Jung, E. Babu, P. Jutabha, S. Khamdang, M. Aleboyeh, M. L. Onodera, A. Tojo, A. Enomoto, N. Anzai, S. Narikawa, X. L. Huang, T. Niwa, and H. Endou. Interactions of human organic anion transporters with diuretics. J. Pharmacol. Exp. Ther (2003).
J. E. van Montfoort, M. Muller, G. M. Groothuis, D. K. Meijer, H. Koepsell, and P. J. Meier. Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J. Pharmacol. Exp. Ther. 298:110-115 (2001).
V. Gorboulev, J. C. Ulzheimer, A. Akhoundova, I. Ulzheimer-Teuber, U. Karbach, S. Quester, C. Baumann, F. Lang, A. E. Busch, and H. Koepsell. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16:871-881 (1997).
D. Grundemann, B. Schechinger, G. A. Rappold, and E. Schomig. Molecular identification of the corticosteronesensitive extraneuronal catecholamine transporter. Nat. Neurosci. 1:349-351 (1998).
D. Grundemann, C. Hahne, R. Berkels, and E. Schomig. Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J. Pharmacol. Exp. Ther. 304:810-817 (2003).
S. P. Cole, K. E. Sparks, K. Fraser, D. W. Loe, C. E. Grant, G. M. Wilson, and R. G. Deeley. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 54:5902-5910 (1994).
K. Koike, T. Kawabe, T. Tanaka, S. Toh, T. Uchiumi, M. Wada, S. Akiyama, M. Ono, and M. Kuwano. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res. 57:5475-5479 (1997).
T. Kawabe, Z. S. Chen, M. Wada, T. Uchiumi, M. Ono, S. Akiyama, and M. Kuwano. Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2). FEBS Lett. 456:327-331 (1999).
L. Payen, A. Courtois, J. P. Campion, A. Guillouzo, and O. Fardel. Characterization and inhibition by a wide range of xenobiotics of organic anion excretion by primary human hepatocytes. Biochem. Pharmacol. 60:1967-1975 (2000).
J. H. Hooijberg, H. J. Broxterman, M. Kool, Y. G. Assaraf, G. J. Peters, P. Noordhuis, R. J. Scheper, P. Borst, H. M. Pinedo, and G. Jansen. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 59:2532-2535 (1999).
R. B. Kim, M. F. Fromm, C. Wandel, B. Leake, A. J. Wood, D. M. Roden, and G. R. Wilkinson. The drug transporter Pglycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289-294 (1998).
J. W. Polli, J. L. Jarrett, S. D. Studenberg, J. E. Humphreys, S. W. Dennis, K. R. Brouwer, and J. L. Woolley. Role of Pglycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm. Res. 16:1206-1212 (1999).
K. Ueda, N. Okamura, M. Hirai, Y. Tanigawara, T. Saeki, N. Kioka, T. Komano, and R. Hori. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J. Biol. Chem. 267:24248-24252 (1992).
J. P. Marie, C. Helou, D. Thevenin, A. Delmer, and R. Zittoun. In vitro effect of P-glycoprotein (P-gp) modulators on drug sensitivity of leukemic progenitors (CFU-L) in acute myelogenous leukemia (AML). Exp. Hematol. 20:565-568 (1992).
R. B. Kim, C. Wandel, B. Leake, M. Cvetkovic, M. F. Fromm, P. J. Dempsey, M. M. Roden, F. Belas, A. K. Chaudhary, D. M. Roden, A. J. Wood, and G. R. Wilkinson. Interrelationship between substrates and inhibitors of human CYP3A and Pglycoprotein. Pharm. Res. 16:408-414 (1999).
M. F. Fromm, R. B. Kim, C. M. Stein, G. R. Wilkinson, and D. M. Roden. Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 99:552-557 (1999).
R. Advani, G. A. Fisher, B. L. Lum, J. Hausdorff, J. Halsey, M. Litchman, and B. I. Sikic. A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance. Clin. Cancer Res. 7:1221-1229 (2001).
I. C. van der Sandt, M. C. Blom-Roosemalen, A. G. de Boer, and D. D. Breimer. Specificity of doxorubicin versus rhodamine-123 in assessing P-glycoprotein functionality in the LLCPK1, LLC-PK1:MDR1 and Caco-2 cell lines. Eur. J. Pharm. Sci. 11:207-214 (2000).
B. L. Lum, G. A. Fisher, N. A. Brophy, A. M. Yahanda, K. M. Adler, S. Kaubisch, J. Halsey, and B. I. Sikic. Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. Cancer 72:3502-3514 (1993).
A. Soldner, U. Christians, M. Susanto, V. J. Wacher, J. A. Silverman, and L. Z. Benet. Grapefruit juice activates Pglycoprotein-mediated drug transport. Pharm. Res. 16:478-485 (1999).
L. C. Floren, I. Bekersky, L. Z. Benet, Q. Mekki, D. Dressler, J. W. Lee, J. P. Roberts, and M. F. Hebert. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin. Pharmacol. Ther. 62:41-49 (1997).
H. Spahn-Langguth, G. Baktir, A. Radschuweit, A. Okyar, B. Terhaag, P. Ader, A. Hanafy, and P. Langguth. P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. Int. J. Clin. Pharmacol. Ther. 36:16-24 (1998).
D. Jung and G. A. Kullak-Ublick. Hepatocyte nuclear factor 1_: a key mediator of the effect of bile acids on gene expression. Hepatology 37:622-631 (2003).
N. J. Cherrington, D. P. Hartley, N. Li, D. R. Johnson, and C. D. Klaassen. Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2 and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J. Pharmacol. Exp. Ther. 300:97-104 (2002).
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Chandra, P., Brouwer, K.L.R. The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts. Pharm Res 21, 719–735 (2004). https://doi.org/10.1023/B:PHAM.0000026420.79421.8f
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DOI: https://doi.org/10.1023/B:PHAM.0000026420.79421.8f