Application of model-based approaches to evaluate Hepatic transporter-mediated drug clearance: In vitro, in vivo, and in vitro-in vivo extrapolation

Current Drug Metabolism

Volumn 17, Issue 5, 2016, Pages 456-468

  Liu, Zhihao ^a   Liu, Kexin ^a  

^a DALIAN MEDICAL UNIVERSITY   (China)

Author keywords

Drug drug interactions; Hepatic transporters; Models; Vitro in vivo extrapolation

Indexed keywords

ABC TRANSPORTER; BILE SALT EXPORT PUMP; BREAST CANCER RESISTANCE PROTEIN; HEPATIC TRANSPORTER; MULTIDRUG RESISTANCE PROTEIN; MULTIDRUG RESISTANCE PROTEIN 1; ORGANIC ANION TRANSPORTING POLYPEPTIDE; POLYPEPTIDE; PROTEIN; SLC22A PROTEIN; SOLUTE CARRIER PROTEIN; UNCLASSIFIED DRUG; CARRIER PROTEIN; DRUG;

CELL ASSAY; DRUG CLEARANCE; DRUG DISPOSITION; IN VITRO IN VIVO EXTRAPOLATION; IN VITRO STUDY; IN VIVO STUDY; ISOLATED PERFUSED LIVER; LIVER CELL; LIVER CELL CULTURE; LIVER PERFUSION; LIVER SLICE; NONHUMAN; PRIMARY CELL; REVIEW; TRANSPORT KINETICS; ANIMAL; BIOLOGICAL MODEL; HUMAN; LIVER; METABOLISM; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; BIOLOGICAL TRANSPORT; HUMANS; LIVER; MEMBRANE TRANSPORT PROTEINS; MODELS, BIOLOGICAL; PHARMACEUTICAL PREPARATIONS;

EID: 84963622985     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/1389200217666160111124139     Document Type: Review

References (144)

1. Shitara, Y.; Horie, T.; Sugiyama, Y. Transporters as a determinant of drug clearance and tissue distribution. Eur. J. Pharm. Sci., 2006, 27(5), 425-446.
2. Caruana, J. A.; Camara, D. S.; Schneeberger, G. J.; Nolan, J. P. The clearance capacity of the canine liver for a portal vein endotoxin infusion. J. Surg. Res., 1984, 37(3), 197-201.
3. Faber, K. N.; Muller, M.; Jansen, P. L. Drug transport proteins in the liver. Adv. Drug Deliv. Rev., 2003, 55(1), 107-124.
4. Chan, L. M.; Lowes, S.; Hirst, B. H. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci., 2004, 21(1), 25-51.
5. Sissung, T. M.; Baum, C. E.; Kirkland, C. T.; Gao, R.; Gardner, E. R.; Figg, W. D. Pharmacogenetics of membrane transporters: an update on current approaches. Mol. Biotechnol., 2010, 44(2), 152-167.
6. Konig, J.; Muller, F.; Fromm, M. F. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol. Rev., 2013, 65(3), 944-966.
7. Bachmakov, I.; Glaeser, H.; Fromm, M. F.; Konig, J. Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes, 2008, 57(6), 1463-1469.
8. Yang, K.; Brouwer, K. L. Hepatocellular exposure of troglitazone metabolites in rat sandwich-cultured hepatocytes lacking Bcrp and Mrp2: interplay between formation and excretion. Drug Metab. Dispos., 2014, 42(7), 1219-1226.
9. Jorgensen, L.; Van Beek, J.; Lund, S.; Schousboe, A.; Badolo, L. Evidence of Oatp and Mdr1 in cryopreserved rat hepatocytes. Eur. J. Pharm. Sci., 2007, 30(2), 181-189.
10. Klaassen, C. D.; Lu, H. Xenobiotic transporters: ascribing function from gene knockout and mutation studies. Toxicol. Sci., 2008, 101(2), 186-196.
11. Tian, X.; Zamek-Gliszczynski, M. J.; Li, J.; Bridges, A. S.; Nezasa, K.; Patel, N. J.; Raub, T. J.; Brouwer, K. L. Multidrug resistanceassociated protein 2 is primarily responsible for the biliary excretion of fexofenadine in mice. Drug Metab. Dispos., 2008, 36(1), 61-64.
12. Kusuhara, H.; Sugiyama, Y. In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab. Pharmacokinet., 2009, 24(1), 37-52.
13. Zhou, Z. W.; Zhou, S. F. Application of mechanism-based CYP inhibition for predicting drug-drug interactions. Expert. Opin. Drug Metab. Toxicol., 2009, 5(6), 579-605.
14. Shen, H.; Yang, Z.; Mintier, G.; Han, Y. H.; Chen, C.; Balimane, P.; Jemal, M.; Zhao, W.; Zhang, R.; Kallipatti, S.; Selvam, S.; Sukrutharaj, S.; Krishnamurthy, P.; Marathe, P.; Rodrigues, A. D. Cynomolgus monkey as a potential model to assess drug interactions involving hepatic organic anion transporting polypeptides: in vitro, in vivo, and in vitro-to-in vivo extrapolation. J. Pharmacol. Exp. Ther., 2013, 344(3), 673-685.
15. Jones, H. M.; Barton, H. A.; Lai, Y.; Bi, Y. A.; Kimoto, E.; Kempshall, S.; Tate, S. C.; El-Kattan, A.; Houston, J. B.; Galetin, A.; Fenner, K. S. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab. Dispos., 2012, 40(5), 1007-1017.
16. Hilgendorf, C.; Ahlin, G.; Seithel, A.; Artursson, P.; Ungell, A. L.; Karlsson, J. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab. Dispos., 2007, 35(8), 1333-1340.
17. Funk, C. The role of hepatic transporters in drug elimination. Expert. Opin. Drug Metab. Toxicol., 2008, 4(4), 363-379.
18. Liu, Z.; Wang, C.; Liu, Q.; Meng, Q.; Cang, J.; Mei, L.; Kaku, T.; Liu, K. Uptake, transport and regulation of JBP485 by PEPT1 in vitro and in vivo. Peptides., 2011, 32(4), 747-754.
19. Zhang, A.; Wang, C.; Liu, Q.; Meng, Q.; Peng, J.; Sun, H.; Ma, X.; Huo, X.; Liu, K. Involvement of organic anion-transporting polypeptides in the hepatic uptake of dioscin in rats and humans. Drug Metab. Dispos., 2013, 41(5), 994-1003.
20. Jacquemin, E.; Hagenbuch, B.; Stieger, B.; Wolkoff, A. W.; Meier, P. J. Expression cloning of a rat liver Na (+)-independent organic anion transporter. Proc. Natl. Acad. Sci. USA, 1994, 91(1), 133-137.
21. Meier-Abt, F.; Mokrab, Y.; Mizuguchi, K. Organic anion transporting polypeptides of the OATP/SLCO superfamily: identification of new members in nonmammalian species, comparative modeling and a potential transport mode. J. Membr. Biol., 2005, 208(3), 213-227.
22. Tamai, I.; Nezu, J.; Uchino, H.; Sai, Y.; Oku, A.; Shimane, M.; Tsuji, A. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem. Biophys. Res. Commun., 2000, 273(1), 251-260.
23. Hagenbuch, B.; Meier, P. J. The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta, 2003, 1609(1), 1-18.
24. Mikkaichi, T.; Suzuki, T.; Tanemoto, M.; Ito, S.; Abe, T. The organic anion transporter (OATP) family. Drug Metab. Pharmacokinet., 2004, 19(3), 171-179.
25. Tamai, I.; Nakanishi, T. OATP transporter-mediated drug absorption and interaction. Curr. Opin. Pharmacol., 2013, 13(6), 859-863.
26. Tamai, I. Oral drug delivery utilizing intestinal OATP transporters. Adv. Drug Deliv. Rev., 2012, 64(6), 508-514.
27. Nakanishi, T.; Tamai, I. Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab. Pharmacokinet., 2012, 27(1), 106-121.
28. Grundemann, D.; Gorboulev, V.; Gambaryan, S.; Veyhl, M.; Koepsell, H. Drug excretion mediated by a new prototype of polyspecific transporter. Nature, 1994, 372(6506), 549-552.
29. Okuda, M.; Saito, H.; Urakami, Y.; Takano, M.; Inui, K. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem. Biophys. Res. Commun., 1996, 224(2), 500-507.
30. Jonker, J. W.; Schinkel, A. H. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J. Pharmacol. Exp. Ther., 2004, 308(1), 2-9.
31. Franke, R. M.; Gardner, E. R.; Sparreboom, A. Pharmacogenetics of drug transporters. Curr. Pharm. Des., 2010, 16(2), 220-230.
32. Zhang, S.; Lovejoy, K. S.; Shima, J. E.; Lagpacan, L. L.; Shu, Y.; Lapuk, A.; Chen, Y.; Komori, T.; Gray, J. W.; Chen, X.; Lippard, S. J.; Giacomini, K. M. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res., 2006, 66(17), 8847-8857.
33. Yonezawa, A.; Masuda, S.; Yokoo, S.; Katsura, T.; Inui, K. 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., 2006, 319(2), 879-886.
34. Szakacs, G.; Varadi, A.; Ozvegy-Laczka, C.; Sarkadi, B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov. Today, 2008, 13(9-10), 379-393.
35. Jia, Y.; Liu, Z.; Huo, X.; Wang, C.; Meng, Q.; Liu, Q.; Sun, H.; Sun, P.; Yang, X.; Shu, X.; Liu, K. Enhancement effect of resveratrol on the intestinal absorption of bestatin by regulating PEPT1, MDR1 and MRP2 in vivo and in vitro. Int. J. Pharm., 2015, 495(1), 588-598.
36. Huo, X.; Liu, Q.; Wang, C.; Meng, Q.; Sun, H.; Peng, J.; Ma, X.; Liu, K. Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin. Eur. J. Pharm. Sci., 2013, 50(3-4), 420-428.
37. Kusuhara, H.; Suzuki, H.; Sugiyama, Y. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci., 1998, 87(9), 1025-1040.
38. Schinkel, A. H.; Mayer, U.; Wagenaar, E.; Mol, C. A.; van Deemter, L.; Smit, J. J.; van der Valk, M. A.; Voordouw, A. C.; Spits, H.; van Tellingen, O.; Zijlmans, J. M.; Fibbe, W. E.; Borst, P. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad. Sci. USA, 1997, 94(8), 4028-4033.
39. Gottesman, M. M.; Pastan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem., 1993, 62, 385-427.
40. Shitara, Y.; Sato, H.; Sugiyama, Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 689-723.
41. Kunta, J. R.; Sinko, P. J. Intestinal drug transporters: in vivo function and clinical importance. Curr. Drug Metab., 2004, 5(1), 109-124.
42. Sparreboom, A.; Danesi, R.; Ando, Y.; Chan, J.; Figg, W. D. Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resist. Updat., 2003, 6(2), 71-84.
43. Ni, Z.; Bikadi, Z.; Rosenberg, M. F.; Mao, Q. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr. Drug Metab., 2010, 11(7), 603-617.
44. Miyake, K.; Mickley, L.; Litman, T.; Zhan, Z.; Robey, R.; Cristensen, B.; Brangi, M.; Greenberger, L.; Dean, M.; Fojo, T.; Bates, S. E. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res., 1999, 59(1), 8-13.
45. Doyle, L. A.; Yang, W.; Abruzzo, L. V.; Krogmann, T.; Gao, Y.; Rishi, A. K.; Ross, D. D. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA, 1998, 95(26), 15665-15670.
46. Ishikawa, T. The role of human ABC transporter ABCG2 (BCRP) in pharmacotherapy. Adv. Drug Deliv. Rev., 2009, 61(1), 1-2.
47. Mao, Q.; Unadkat, J. D. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport-an update. AAPS J., 2015, 17(1), 65-82.
48. Robey, R. W.; To, K. K.; Polgar, O.; Dohse, M.; Fetsch, P.; Dean, M.; Bates, S. E. ABCG2: a perspective. Adv. Drug Deliv. Rev., 2009, 61(1), 3-13.
49. Ejendal, K. F.; Hrycyna, C. A. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr. Protein Pept. Sci., 2002, 3(5), 503-511.
50. Yu, X. Q.; Xue, C. C.; Wang, G.; Zhou, S. F. Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs. Curr. Drug Metab., 2007, 8(8), 787-802.
51. Higgins, C. F. ABC transporters: from microorganisms to man. Annu. Rev. Cell. Biol., 1992, 8, 67-113.
52. Buchler, M.; Konig, J.; Brom, M.; Kartenbeck, J.; Spring, H.; Horie, T.; Keppler, D. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J. Biol. Chem., 1996, 271(25), 15091-15098.
53. Nakamura, T.; Yamamori, M.; Sakaeda, T. Pharmacogenetics of intestinal absorption. Curr. Drug Deliv., 2008, 5(3), 153-169.
54. Slot, A. J.; Molinski, S. V.; Cole, S. P. Mammalian multidrugresistance proteins (MRPs). Essays. Biochem., 2011, 50(1), 179-207.
55. Vadlapatla, R. K.; Vadlapudi, A. D.; Kwatra, D.; Pal, D.; Mitra, A. K. Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin. Int. J. Pharm., 2011, 420(1), 26-33.
56. Lam, P.; Soroka, C. J.; Boyer, J. L. The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin. Liver Dis., 2010, 30(2), 125-133.
57. Gerloff, T.; Stieger, B.; Hagenbuch, B.; Madon, J.; Landmann, L.; Roth, J.; Hofmann, A. F.; Meier, P. J. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem., 1998, 273(16), 10046-10050.
58. Strautnieks, S. S.; Bull, L. N.; Knisely, A. S.; Kocoshis, S. A.; Dahl, N.; Arnell, H.; Sokal, E.; Dahan, K.; Childs, S.; Ling, V.; Tanner, M. S.; Kagalwalla, A. F.; Nemeth, A.; Pawlowska, J.; Baker, A.; Mieli-Vergani, G.; Freimer, N. B.; Gardiner, R. M.; Thompson, R. J. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet., 1998, 20(3), 233-238.
59. Chen, X.; Meng, Q.; Wang, C.; Liu, Q.; Sun, H.; Huo, X.; Sun, P.; Yang, X.; Peng, J.; Liu, K. Protective effects of calycosin against CCl4-induced liver injury with activation of FXR and STAT3 in mice. Pharm. Res., 2015, 32(2), 538-548.
60. Lecureur, V.; Sun, D.; Hargrove, P.; Schuetz, E. G.; Kim, R. B.; Lan, L. B.; Schuetz, J. D. Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol. Pharmacol., 2000, 57(1), 24-35.
61. Wang, E. J.; Casciano, C. N.; Clement, R. P.; Johnson, W. W. Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm. Res., 2003, 20(4), 537-544.
62. Hirano, M.; Maeda, K.; Hayashi, H.; Kusuhara, H.; Sugiyama, Y. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J. Pharmacol. Exp. Ther., 2005, 314(2), 876-882.
63. Kitamura, S.; Maeda, K.; Sugiyama, Y. Recent progresses in the experimental methods and evaluation strategies of transporter functions for the prediction of the pharmacokinetics in humans. Naunyn. Schmiedebergs. Arch. Pharmacol., 2008, 377(4-6), 617-628.
64. Zamek-Gliszczynski, M. J.; Lee, C. A.; Poirier, A.; Bentz, J.; Chu, X.; Ellens, H.; Ishikawa, T.; Jamei, M.; Kalvass, J. C.; Nagar, S.; Pang, K. S.; Korzekwa, K.; Swaan, P. W.; Taub, M. E.; Zhao, P.; Galetin, A. ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin. Pharmacol. Ther., 2013, 94(1), 64-79.
65. Nakamura, T.; Yonezawa, A.; Hashimoto, S.; Katsura, T.; Inui, K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem. Pharmacol., 2010, 80(11), 1762-1767.
66. Hirouchi, M.; Kusuhara, H.; Onuki, R.; Ogilvie, B. W.; Parkinson, A.; Sugiyama, Y. Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistanceassociated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4. Drug Metab. Dispos., 2009, 37(10), 2103-2111.
67. Ye, J.; Liu, Q.; Wang, C.; Meng, Q.; Peng, J.; Sun, H.; Kaku, T.; Liu, K. Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3. Eur. J. Pharm. Sci., 2012, 47(2), 341-346.
68. Xia, C. Q.; Milton, M. N.; Gan, L. S. Evaluation of drug-transporter interactions using in vitro and in vivo models. Curr. Drug Metab., 2007, 8(4), 341-363.
69. Sheng, J.; Tian, X.; Xu, G.; Wu, Z.; Chen, C.; Wang, L.; Pan, L.; Huang, C.; Pan, G. The hepatobiliary disposition of timosaponin b2 is highly dependent on influx/efflux transporters but not metabolism. Drug Metab. Dispos., 2015, 43(1), 63-72.
70. Kitamura, S.; Maeda, K.; Wang, Y.; Sugiyama, Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab. Dispos., 2008, 36(10), 2014-2023.
71. Varma, M. V.; Lai, Y.; Feng, B.; Litchfield, J.; Goosen, T. C.; Bergman, A. Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions. Pharm. Res., 2012, 29(10), 2860-2873.
72. Iwai, M.; Minematsu, T.; Li, Q.; Iwatsubo, T.; Usui, T. Utility of P-glycoprotein and organic cation transporter 1 double-transfected LLC-PK1 cells for studying the interaction of YM155 monobromide, novel small-molecule survivin suppressant, with P-glycoprotein. Drug Metab. Dispos., 2011, 39(12), 2314-2320.
73. Gottlieb, T. A.; Beaudry, G.; Rizzolo, L.; Colman, A.; Rindler, M.; Adesnik, M.; Sabatini, D. D. Secretion of endogenous and exogenous proteins from polarized MDCK cell monolayers. Proc. Natl. Acad. Sci. USA, 1986, 83(7), 2100-2104.
74. Ahlin, G.; Hilgendorf, C.; Karlsson, J.; Szigyarto, C. A.; Uhlen, M.; Artursson, P. Endogenous gene and protein expression of drugtransporting proteins in cell lines routinely used in drug discovery programs. Drug Metab. Dispos., 2009, 37(12), 2275-2283.
75. Brouwer, K. L.; Keppler, D.; Hoffmaster, K. A.; Bow, D. A.; Cheng, Y.; Lai, Y.; Palm, J. E.; Stieger, B.; Evers, R. In vitro methods to support transporter evaluation in drug discovery and development. Clin. Pharmacol. Ther., 2013, 94(1), 95-112.
76. Hoffmaster, K. A.; Turncliff, R. Z.; LeCluyse, E. L.; Kim, R. B.; Meier, P. J.; Brouwer, K. L. P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Pharm. Res., 2004, 21(7), 1294-1302.
77. Yabe, Y.; Galetin, A.; Houston, J. B. Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metab. Dispos., 2011, 39(10), 1808-1814.
78. Lam, J. L.; Benet, L. Z. Hepatic microsome studies are insufficient to characterize in vivo hepatic metabolic clearance and metabolic drug-drug interactions: studies of digoxin metabolism in primary rat hepatocytes versus microsomes. Drug Metab. Dispos., 2004, 32(11), 1311-1316.
79. Menochet, K.; Kenworthy, K. E.; Houston, J. B.; Galetin, A. Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab. Dispos., 2012, 40(9), 1744-1756.
80. Yamashiro, W.; Maeda, K.; Hirouchi, M.; Adachi, Y.; Hu, Z.; Sugiyama, Y. 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., 2006, 34(7), 1247-1254.
81. Bow, D. A.; Perry, J. L.; Miller, D. S.; Pritchard, J. B.; Brouwer, K. L. Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in freshly isolated rat hepatocytes. Drug Metab. Dispos., 2008, 36(1), 198-202.
82. Houle, R.; Raoul, J.; Levesque, J. F.; Pang, K. S.; Nicoll-Griffith, D. A.; Silva, J. M. Retention of transporter activities in cryopreserved, isolated rat hepatocytes. Drug Metab. Dispos., 2003, 31(4), 447-451.
83. Swift, B.; Pfeifer, N. D.; Brouwer, K. L. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporterbased drug interactions and hepatotoxicity. Drug Metab. Rev., 2010, 42(3), 446-471.
84. Kimoto, E.; Yoshida, K.; Balogh, L. M.; Bi, Y. A.; Maeda, K.; El-Kattan, A.; Sugiyama, Y.; Lai, Y. Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol. Pharm., 2012, 9(12), 3535-3542.
85. Abe, K.; Bridges, A. S.; Brouwer, K. L. Use of sandwich-cultured human hepatocytes to predict biliary clearance of angiotensin II receptor blockers and HMG-CoA reductase inhibitors. Drug Metab. Dispos., 2009, 37(3), 447-452.
86. Matsunaga, N.; Wada, S.; Nakanishi, T.; Ikenaga, M.; Ogawa, M.; Tamai, I. Mathematical modeling of the in vitro hepatic disposition of mycophenolic acid and its glucuronide in sandwich-cultured human hepatocytes. Mol. Pharm., 2014, 11(2), 568-579.
87. Picard, N.; Yee, S. W.; Woillard, J. B.; Lebranchu, Y.; Le Meur, Y.; Giacomini, K. M.; Marquet, P. The role of organic aniontransporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin. Pharmacol. Ther., 2010, 87(1), 100-108.
88. Yue, W.; Abe, K.; Brouwer, K. L. Knocking down breast cancer resistance protein (Bcrp) by adenoviral vector-mediated RNA interference (RNAi) in sandwich-cultured rat hepatocytes: a novel tool to assess the contribution of Bcrp to drug biliary excretion. Mol. Pharm., 2009, 6(1), 134-143.
89. Liao, M.; Raczynski, A. R.; Chen, M.; Chuang, B. C.; Zhu, Q.; Shipman, R.; Morrison, J.; Lee, D.; Lee, F. W.; Balani, S. K.; Xia, C. Q. Inhibition of hepatic organic anion-transporting polypeptide by RNA interference in sandwich-cultured human hepatocytes: an in vitro model to assess transporter-mediated drug-drug interactions. Drug Metab. Dispos., 2010, 38(9), 1612-1622.
90. Lepist, E. I.; Gillies, H.; Smith, W.; Hao, J.; Hubert, C.; St Claire, R. L., 3rd; Brouwer, K. R.; Ray, A. S. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One, 2014, 9(1), e87548.
91. Li, N.; Bi, Y. A.; Duignan, D. B.; Lai, Y. Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol. Pharm., 2009, 6(4), 1180-1189.
92. Borlak, J.; Klutcka, T. Expression of basolateral and canalicular transporters in rat liver and cultures of primary hepatocytes. Xenobiotica., 2004, 34(11-12), 935-947.
93. Kotani, N.; Maeda, K.; Watanabe, T.; Hiramatsu, M.; Gong, L. K.; Bi, Y. A.; Takezawa, T.; Kusuhara, H.; Sugiyama, Y. Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes. Drug Metab. Dispos., 2011, 39(9), 1503-1510.
94. Tchaparian, E. H.; Houghton, J. S.; Uyeda, C.; Grillo, M. P.; Jin, L. Effect of culture time on the basal expression levels of drug transporters in sandwich-cultured primary rat hepatocytes. Drug Metab. Dispos., 2011, 39(12), 2387-2394.
95. Rothbarth, J.; Tollenaar, R. A.; Schellens, J. H.; Nortier, J. W.; Kool, L. J.; Kuppen, P. J.; Mulder, G. J.; van de Velde, C. J. Isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: recent trends and perspectives. Eur. J. Cancer, 2004, 40(12), 1812-1824.
96. Hafstrom, L. R.; Holmberg, S. B.; Naredi, P. L.; Lindner, P. G.; Bengtsson, A.; Tidebrant, G.; Schersten, T. S. Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. Surg. Oncol., 1994, 3(2), 103-108.
97. Dinan, N. M.; Atyabi, F.; Rouini, M. R.; Amini, M.; Golabchifar, A. A.; Dinarvand, R. Doxorubicin loaded folate-targeted carbon nanotubes: preparation, cellular internalization, in vitro cytotoxicity and disposition kinetic study in the isolated perfused rat liver. Mater. Sci. Eng. C Mater. Biol. Appl., 2014, 39, 47-55.
98. Bessems, M.; t Hart, N. A.; Tolba, R.; Doorschodt, B. M.; Leuvenink, H. G.; Ploeg, R. J.; Minor, T.; van Gulik, T. M. The isolated perfused rat liver: standardization of a time-honoured model. Lab. Anim., 2006, 40(3), 236-246.
99. Minor, T.; Manekeller, S. Assessment of hepatic integrity after ischemic preservation by isolated perfusion in vitro: the role of albumin. Cryobiology, 2007, 54(2), 188-195.
100. Zamek-Gliszczynski, M. J.; Hoffmaster, K. A.; Humphreys, J. E.; Tian, X.; Nezasa, K.; Brouwer, K. L. Differential involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in biliary excretion of 4-methylumbelliferyl glucuronide and sulfate in the rat. J. Pharmacol. Exp. Ther., 2006, 319(1), 459-467.
101. Parasrampuria, R.; Mehvar, R. Dose-dependent inhibition of transporter-mediated hepatic uptake and biliary excretion of methotrexate by cyclosporine A in an isolated perfused rat liver model. J. Pharm. Sci., 2010, 99(12), 5060-5069.
102. Hobbs, M.; Parker, C.; Birch, H.; Kenworthy, K. Understanding the interplay of drug transporters involved in the disposition of rosuvastatin in the isolated perfused rat liver using a physiologically-based pharmacokinetic model. Xenobiotica, 2012, 42(4), 327-338.
103. Groneberg, D. A.; Grosse-Siestrup, C.; Fischer, A. In vitro models to study hepatotoxicity. Toxicol. Pathol., 2002, 30(3), 394-399.
104. Olinga, P.; Hof, I. H.; Merema, M. T.; Smit, M.; de Jager, M. H.; Swart, P. J.; Slooff, M. J.; Meijer, D. K.; Groothuis, G. M. The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake. J. Pharmacol. Toxicol. Methods, 2001, 45(1), 55-63.
105. van de Bovenkamp, M.; Groothuis, G. M.; Meijer, D. K.; Slooff, M. J.; Olinga, P. Human liver slices as an in vitro model to study toxicity-induced hepatic stellate cell activation in a multicellular milieu. Chem. Biol. Interact., 2006, 162(1), 62-69.
106. Elferink, M. G.; Olinga, P.; Draaisma, A. L.; Merema, M. T.; Faber, K. N.; Slooff, M. J.; Meijer, D. K.; Groothuis, G. M. LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 287(5), G1008-1016.
107. Poirier, A.; Lave, T.; Portmann, R.; Brun, M. E.; Senner, F.; Kansy, M.; Grimm, H. P.; Funk, C. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metab. Dispos., 2008, 36(12), 2434-2444.
108. Sun, P.; Wang, C.; Liu, Q.; Meng, Q.; Zhang, A.; Huo, X.; Sun, H.; Liu, K. OATP and MRP2-mediated hepatic uptake and biliary excretion of eprosartan in rat and human. Pharmacol. Rep., 2014, 66(2), 311-319.
109. Tian, X.; Li, J.; Zamek-Gliszczynski, M. J.; Bridges, A. S.; Zhang, P.; Patel, N. J.; Raub, T. J.; Pollack, G. M.; Brouwer, K. L. Roles of P-glycoprotein, Bcrp, and Mrp2 in biliary excretion of spiramycin in mice. Antimicrob. Agents Chemother., 2007, 51(9), 3230-3234.
110. Iusuf, D.; Hendrikx, J. J.; van Esch, A.; van de Steeg, E.; Wagenaar, E.; Rosing, H.; Beijnen, J. H.; Schinkel, A. H. Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int. J. Cancer, 2015, 136(1), 225-233.
111. Jonker, J. W.; Wagenaar, E.; Mol, C. A.; Buitelaar, M.; Koepsell, H.; Smit, J. W.; Schinkel, A. H. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol. Cell. Biol., 2001, 21(16), 5471-5477.
112. Xiong, H.; Suzuki, H.; Sugiyama, Y.; Meier, P. J.; Pollack, G. M.; Brouwer, K. L. Mechanisms of impaired biliary excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment. Drug Metab. Dispos., 2002, 30(9), 962-969.
113. Yue, W.; Lee, J. K.; Abe, K.; Sugiyama, Y.; Brouwer, K. L. Decreased hepatic breast cancer resistance protein expression and function in multidrug resistance-associated protein 2-deficient (TR (-)) rats. Drug Metab. Dispos., 2011, 39(3), 441-447.
114. Zimmermann, C.; van de Wetering, K.; van de Steeg, E.; Wagenaar, E.; Vens, C.; Schinkel, A. H. Species-dependent transport and modulation properties of human and mouse multidrug resistance protein 2 (MRP2/Mrp2, ABCC2/Abcc2). Drug Metab. Dispos., 2008, 36(4), 631-640.
115. van de Steeg, E.; van der Kruijssen, C. M.; Wagenaar, E.; Burggraaff, J. E.; Mesman, E.; Kenworthy, K. E.; Schinkel, A. H. Methotrexate pharmacokinetics in transgenic mice with liverspecific expression of human organic anion-transporting polypeptide 1B1 (SLCO1B1). Drug Metab. Dispos., 2009, 37(2), 277-281.
116. van de Steeg, E.; van Esch, A.; Wagenaar, E.; Kenworthy, K. E.; Schinkel, A. H. Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin. Cancer Res., 2013, 19(4), 821-832.
117. van de Steeg, E.; Stranecky, V.; Hartmannova, H.; Noskova, L.; Hrebicek, M.; Wagenaar, E.; van Esch, A.; de Waart, D. R.; Oude Elferink, R. P.; Kenworthy, K. E.; Sticova, E.; al-Edreesi, M.; Knisely, A. S.; Kmoch, S.; Jirsa, M.; Schinkel, A. H. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J. Clin. Invest., 2012, 122(2), 519-528.
118. Salphati, L.; Chu, X.; Chen, L.; Prasad, B.; Dallas, S.; Evers, R.; Mamaril-Fishman, D.; Geier, E. G.; Kehler, J.; Kunta, J.; Mezler, M.; Laplanche, L.; Pang, J.; Rode, A.; Soars, M. G.; Unadkat, J. D.; van Waterschoot, R. A.; Yabut, J.; Schinkel, A. H.; Scheer, N. Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins. Drug Metab. Dispos., 2014, 42(8), 1301-1313.
119. Higgins, J. W.; Bao, J. Q.; Ke, A. B.; Manro, J. R.; Fallon, J. K.; Smith, P. C.; Zamek-Gliszczynski, M. J. Utility of Oatp1a/1bknockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein. Drug Metab. Dispos., 2014, 42(1), 182-192.
120. Karlgren, M.; Ahlin, G.; Bergstrom, C. A.; Svensson, R.; Palm, J.; Artursson, P. In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions. Pharm. Res., 2012, 29(2), 411-426.
121. Watanabe, T.; Kusuhara, H.; Maeda, K.; Shitara, Y.; Sugiyama, Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J. Pharmacol. Exp. Ther., 2009, 328(2), 652-662.
122. Umehara, K.; Camenisch, G. Novel in vitro-in vivo extrapolation (IVIVE) method to predict hepatic organ clearance in rat. Pharm. Res., 2012, 29(2), 603-617.
123. Food and Drug Administration. Drug interaction studies-study design, data analysis, implications for dosing, and labeling recommendations. Guidance for Industry. 2012, (http://www.fda. gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
124. Ito, K.; Iwatsubo, T.; Kanamitsu, S.; Ueda, K.; Suzuki, H.; Sugiyama, Y. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol. Rev., 1998, 50(3), 387-412.
125. Matsushima, S.; Maeda, K.; Ishiguro, N.; Igarashi, T.; Sugiyama, Y. Investigation of the inhibitory effects of various drugs on the hepatic uptake of fexofenadine in humans. Drug Metab. Dispos., 2008, 36(4), 663-669.
126. Giacomini, K. M.; Huang, S. M.; Tweedie, D. J.; Benet, L. Z.; Brouwer, K. L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.; Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.; Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drug development. Nat. Rev. Drug Discov., 2010, 9(3), 215-236.
127. Hirano, M.; Maeda, K.; Shitara, Y.; Sugiyama, Y. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab. Dispos., 2006, 34(7), 1229-1236.
128. Lau, Y. Y.; Huang, Y.; Frassetto, L.; Benet, L. Z. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin. Pharmacol. Ther., 2007, 81(2), 194-204.
129. Sharma, P.; Butters, C. J.; Smith, V.; Elsby, R.; Surry, D. Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. Eur. J. Pharm. Sci., 2012, 47(1), 244-255.
130. Sasaki, M.; Suzuki, H.; Aoki, J.; Ito, K.; Meier, P. J.; Sugiyama, Y. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol. Pharmacol., 2004, 66(3), 450-459.
131. Kusuhara, H.; Sugiyama, Y. Pharmacokinetic modeling of the hepatobiliary transport mediated by cooperation of uptake and efflux transporters. Drug Metab. Rev., 2010, 42(3), 539-550.
132. Kock, K.; Xie, Y.; Hawke, R. L.; Oberlies, N. H.; Brouwer, K. L. Interaction of silymarin flavonolignans with organic aniontransporting polypeptides. Drug Metab. Dispos., 2013, 41(5), 958-965.
133. Chen, Y.; Jin, J. Y.; Mukadam, S.; Malhi, V.; Kenny, J. R. Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies. Biopharm. Drug Dispos., 2012, 33(2), 85-98.
134. Varma, M. V.; Lin, J.; Bi, Y. A.; Rotter, C. J.; Fahmi, O. A.; Lam, J. L.; El-Kattan, A. F.; Goosen, T. C.; Lai, Y. Quantitative prediction of repaglinide-rifampicin complex drug interactions using dynamic and static mechanistic models: delineating differential CYP3A4 induction and OATP1B1 inhibition potential of rifampicin. Drug Metab. Dispos., 2013, 41(5), 966-974.
135. Mao, J.; Johnson, T. R.; Shen, Z.; Yamazaki, S. Prediction of crizotinib-midazolam interaction using the Simcyp populationbased simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes. Drug Metab. Dispos., 2013, 41(2), 343-352.
136. Wang, Q.; Strab, R.; Kardos, P.; Ferguson, C.; Li, J.; Owen, A.; Hidalgo, I. J. Application and limitation of inhibitors in drugtransporter interactions studies. Int. J. Pharm., 2008, 356(1-2), 12-18.
137. Barton, H. A.; Lai, Y.; Goosen, T. C.; Jones, H. M.; El-Kattan, A. F.; Gosset, J. R.; Lin, J.; Varma, M. V. Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert. Opin. Drug Metab. Toxicol., 2013, 9(4), 459-472.
138. Li, N.; Singh, P.; Mandrell, K. M.; Lai, Y. Improved extrapolation of hepatobiliary clearance from in vitro sandwich cultured rat hepatocytes through absolute quantification of hepatobiliary transporters. Mol. Pharm., 2010, 7(3), 630-641.
139. Jani, M.; Krajcsi, P. In vitro methods in drug transporter interaction assessment. Drug Discov. Today Technol., 2014, 12, e105-112.
140. Feng, B.; Varma, M. V.; Costales, C.; Zhang, H.; Tremaine, L. In vitro and in vivo approaches to characterize transporter-mediated disposition in drug discovery. Expert. Opin. Drug Discov., 2014, 9(8), 873-890.
141. Chu, X.; Korzekwa, K.; Elsby, R.; Fenner, K.; Galetin, A.; Lai, Y.; Matsson, P.; Moss, A.; Nagar, S.; Rosania, G. R.; Bai, J. P.; Polli, J. W.; Sugiyama, Y.; Brouwer, K. L. Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin. Pharmacol. Ther., 2013, 94(1), 126-141.
142. Wang, L.; Prasad, B.; Salphati, L.; Chu, X.; Gupta, A.; Hop, C. E.; Evers, R.; Unadkat, J. D. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab. Dispos., 2015, 43(3), 367-374.
143. Chu, X.; Bleasby, K.; Evers, R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert. Opin. Drug Metab. Toxicol., 2013, 9(3), 237-252.
144. Cohen, J. Toxicology. 'Humanized' mouse detects deadly drug side effects. Science, 2014, 344(6181), 244-245.