Evaluation of adverse drug properties with cryopreserved human hepatocytes and the integrated discrete multiple organ co-culture (IdMOC™) system

Toxicological Research

Volumn 31, Issue 2, 2015, Pages 137-149

  Li, Albert P ^a  

^a In Vitro ADMET Laboratories LLC   (United States)

Author keywords

Drug development; Drug metabolism; Drug toxicity; Drug drug interactions; Hepatocyte cryopreservation; Human hepatocytes; IdMOC

Indexed keywords

EID: 84937954629     PISSN: 19768257     EISSN: 22342753     Source Type: Journal    
DOI: 10.5487/TR.2015.31.2.137     Document Type: Article

References (127)

1. Kola, I. and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery, 3, 711-715.
2. Li, A.P. (2004) Accurate prediction of human drug toxicity: a major challenge in drug development. Chem. Biol. Interact., 150, 3-7.
3. Li, A.P. (2010) Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol. Biol., 640, 281-294.
4. Baillie, T.A. and Rettie, A.E. (2011) Role of biotransformation in drug-induced toxicity: influence of intra- and interspecies differences in drug metabolism. Drug Metab. Pharmacokinet., 26, 15-29.
5. Easterbrook, J., Fackett, D. and Li, A.P. (2001) A comparison of aroclor 1254-induced and uninduced rat liver microsomes to human liver microsomes in phenytoin O-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, Smephenytoin 4'-hydroxylation, chloroxazone 6-hydroxylation and testosterone 6beta-hydroxylation. Chem. Biol. Interact., 134, 243-249.
6. Lee, K., Vandenberghe, Y., Herin, M., Cavalier, R., Beck, D., Li, A., Verbeke, N., Lesne, M. and Roba, J. (1994) Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonists, in rat and human hepatocyte cultures. Xenobiotica, 24, 25-36.
7. Montastruc, F., Sommet, A., Bondon-Guitton, E., Durrieu, G., Bui, E., Bagheri, H., Lapeyre-Mestre, M., Schmitt, L. and Montastruc, J.L. (2012) The importance of drug-drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France. Eur. J. Clin. Pharmacol., 68, 767-775.
8. Takarabe, M., Shigemizu, D., Kotera, M., Goto, S. and Kanehisa, M. (2011) Network-based analysis and characterization of adverse drug-drug interactions. J. Chem. Inf. Model., 51, 2977-2985.
9. Assis, D.N. and Navarro, V.J. (2009) Human drug hepatotoxicity:a contemporary clinical perspective. Expert. Opin. Drug Metab. Toxicol., 5, 463-473.
10. Kaplowitz, N. (2013) Avoiding idiosyncratic DILI: two is better than one. Hepatology, 58, 15-17.
11. Stephens, C., Lucena, M.I. and Andrade, R.J. (2012) Genetic variations in drug-induced liver injury (DILI): resolving the puzzle. Front. Genet., 3, 253.
12. Hawkins, M.T. and Lewis, J.H. (2012) Latest advances in predicting DILI in human subjects: focus on biomarkers. Expert. Opin. Drug Metab. Toxicol., 8, 1521-1530.
13. Li, A.P. (2008) Human hepatocytes as an effective alternative experimental system for the evaluation of human drug properties:general concepts and assay procedures. Altex, 25, 33-42.
14. Li, A.P. (2007) Human hepatocytes: isolation, cryopreservation and applications in drug development. Chem. Biol. Interact., 168, 16-29.
15. Gómez-Lechón, M.J., Lahoz, A., Jiménez, N., Vicente Castell, J. and Donato, M.T. (2006) Cryopreservation of rat, dog and human hepatocytes: influence of preculture and cryoprotectants on recovery, cytochrome P450 activities and induction upon thawing. Xenobiotica, 36, 457-472.
16. Terry, C., Mitry, R.R., Lehec, S.C., Muiesan, P., Rela, M., Heaton, N.D., Hughes, R.D. and Dhawan A. (2005) The effects of cryopreservation on human hepatocytes obtained from different sources of liver tissue. Cell Transplant., 14, 585-594.
17. De Bruyn, T., Ye, Z.W., Peeters, A., Sahi, J., Baes, M., Augustijns, P.F. and Annaert, P.P. (2011) Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. Eur. J. Pharm. Sci., 43, 297-307.
18. Kimoto, E., Yoshida, K., Balogh, L.M., Bi, Y.A., Maeda, K., El-Kattan, A., Sugiyama, Y. and Lai, Y. (2012) Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol. Pharmaceutics, 9, 3535-3542.
19. Maeda, K., Kambara, M., Tian, Y., Hofmann, A.F. and Sugiyama, Y. (2006) 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. Pharmaceutics, 3, 70-77.
20. Shitara, Y., Li, A.P., Kato, Y., Lu, C., Ito, K., Itoh, T. and Sugiyama, Y. (2003) Function of uptake transporters for taurocholate and estradiol 17beta-D-glucuronide in cryopreserved human hepatocytes. Drug Metab. Pharmacokinet., 18, 33-41.
21. Li, N., Zhang, Y., Hua, F. and Lai, Y. (2009) Absolute difference of hepatobiliary transporter multidrug resistance-associated protein (MRP2/Mrp2) in liver tissues and isolated hepatocytes from rat, dog, monkey, and human. Drug Metab. Dispos., 37, 66-73.
22. Li, M., Yuan, H., Li, N., Song, G., Zheng, Y., Baratta, M., Hua, F., Thurston, A., Wang, J. and Lai, Y. (2008) Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human. Eur. J. Pharm. Sci., 35, 114-126.
23. Bi, Y.A., Kazolias, D. and Duignan, D.B. (2006) Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab. Dispos., 34, 1658-1665.
24. Chen, Y., Liu, L., Monshouwer, M. and Fretland, A.J. (2011) Determination of time-dependent inactivation of CYP3A4 in cryopreserved human hepatocytes and assessment of human drug-drug interactions. Drug Metab. Dispos., 39, 2085-2092.
25. Xu, L., Chen, Y., Pan, Y., Skiles, G.L. and Shou, M. (2009) Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab. Dispos., 37, 2330-2339.
26. Li, A.P. and Doshi, U. (2011) Higher throughput human hepatocyte assays for the evaluation of time-dependent inhibition of CYP3A4. Drug Metab. Lett., 5, 183-191.
27. McGinnity, D.F., Berry, A.J., Kenny, J.R., Grime, K. and Riley, R.J. (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab. Dispos., 34, 1291-1300.
28. Zhao, P., Kunze, K.L. and Lee, C.A. (2005) Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab. Dispos., 33, 853-861.
29. Li, A.P. (2009) Metabolism comparative cytotoxicity assay (MCCA) and cytotoxic metabolic pathway identification assay (CMPIA) with cryopreserved human hepatocytes for the evaluation of metabolism-based cytotoxicity in vitro: proofof- concept study with aflatoxin B1. Chem. Biol. Interact., 179, 4-8.
30. Li, A.P., Uzgare, A. and LaForge, Y.S. (2012) Definition of metabolism-dependent xenobiotic toxicity with co-cultures of human hepatocytes and mouse 3T3 fibroblasts in the novel integrated discrete multiple organ co-culture (IdMOC) experimental system: results with model toxicants aflatoxin B1, cyclophosphamide and tamoxifen. Chem. Biol. Interact., 199, 1-8.
31. Webb, D.J., Freestone, S., Allen, M.J. and Muirhead, G.J. (1999) Sildenafil citrate and blood-pressure-lowering drugs:results of drug interaction studies with an organic nitrate and a calcium antagonist. Am. J. Cardiol., 83, 21C-28C.
32. Li, A.P., Kaminski, D.L. and Rasmussen, A. (1995) Substrates of human hepatic cytochrome P450 3A4. Toxicology, 104, 1-8.
33. Zimmermann, M., Duruz, H., Guinand, O., Broccard, O., Levy, P., Lacatis, D. and Bloch, A. (1992) Torsades de Pointes after treatment with terfenadine and ketoconazole. Eur. Heart J., 13, 1002-1003.
34. Flockhart, D.A. (1996) Drug interactions, cardiac toxicity, and terfenadine: from bench to clinic? J. Clin. Psychopharmacol., 16, 101-103.
35. Ishizaki, T. (1996) Strategic proposals to avoid drug interactions during drug development: a lesson from a terfenadinerelated drug interaction. J. Toxicol. Sci., 21, 301-303.
36. Terrien, M.H., Rahm, F., Fellrath, J.M. and Spertini, F. (1999) Comparison of the effects of terfenadine with fexofenadine on nasal provocation tests with allergen. J. Allergy Clin. Immunol., 103, 1025-1030.
37. Borcherding, S.M., Baciewicz, A.M. and Self, T.H. (1992) Update on rifampin drug interactions. II. Arch. Intern. Med., 152, 711-716.
38. Holdiness, M.R. (1987) Rifampin drug interactions. Arch. Intern. Med., 147, 1856.
39. Baciewicz, A.M., Self, T.H. and Bekemeyer, W.B. (1987) Update on rifampin drug interactions. Arch. Intern. Med., 147, 565-568.
40. Baciewicz, A.M. and Self, T.H. (1984) Rifampin drug interactions. Arch. Intern. Med., 144, 1667-1671.
41. Offermann, G., Keller, F. and Molzahn, M. (1985) Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am. J. Nephrol., 5, 385-387.
42. Müller, F. and Fromm, M.F. (2011) Transporter-mediated drug-drug interactions. Pharmacogenomics, 12, 1017-1037.
43. Zhang, L., Huang, S.M. and Lesko, L.J. (2011) Transportermediated drug-drug interactions. Clin. Pharmacol. Ther., 89, 481-484.
44. Lai, Y., Sampson, K.E. and Stevens, J.C. (2010) Evaluation of drug transporter interactions in drug discovery and development. Comb. Chem. High Throughput Screening, 13, 112-134.
45. Tsuji, A. (2002) Transporter-mediated Drug Interactions. Drug Metab. Pharmacokinet., 17, 253-274.
46. Maeda, K. and Sugiyama, Y. (2013) Transporter biology in drug approval: regulatory aspects. Mol. Aspects Med., 34, 711-718.
47. Zamek-Gliszczynski, M.J., Hoffmaster, K.A., Tweedie, D.J., Giacomini, K.M. and Hillgren, K.M. (2012) Highlights from the International Transporter Consortium second workshop. Clin. Pharmacol. Ther., 92, 553-556.
48. Zhang, L., Zhang, Y.D., Strong, J.M., Reynolds, K.S. and Huang, S.M. (2008) A regulatory viewpoint on transporterbased drug interactions. Xenobiotica, 38, 709-724.
49. Lee, J.I., Zhang, L., Men, A.Y., Kenna, L.A. and Huang, S.M. (2010) CYP-mediated therapeutic protein-drug interactions:clinical findings, proposed mechanisms and regulatory implications. Clin. Pharmacokinet., 49, 295-310.
50. Zhang, L., Zhang, Y. and Huang, S.M. (2009) Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol. Pharmaceutics, 6, 1766-1774.
51. Müller, H.J. and Gundert-Remy, U. (1994) The regulatory view on drug-drug interactions. Int. J. Clin. Pharmacol. Ther., 32, 269-273.
52. Darnell, M., Ulvestad, M., Ellis, E., Weidolf, L. and Andersson, T.B. (2012) In vitro evaluation of major in vivo drug metabolic pathways using primary human hepatocytes and HepaRG cells in suspension and a dynamic three-dimensional bioreactor system. J. Pharmacol. Exp. Ther., 343, 134-144.
53. Gómez-Lechón, M.J., Donato, M.T., Castell, J.V. and Jover, R. (2004) Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr. Drug Metab., 5, 443-462.
54. Hong, H., Su, H., Ma, L., Yao, M., Iyer, R.A., Humphreys, W.G. and Christopher, L.J. (2011) In vitro characterization of the metabolic pathways and cytochrome P450 inhibition and induction potential of BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor. Drug Metab. Dispos., 39, 1658-1667.
55. Khojasteh, S.C., Prabhu, S., Kenny, J.R., Halladay, J.S. and Lu, A.Y. (2011) Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet., 36, 1-16.
56. Parkinson, A., Kazmi, F., Buckley, D.B., Yerino, P., Ogilvie, B.W. and Paris, B.L. (2010) System-dependent outcomes during the evaluation of drug candidates as inhibitors of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes: human hepatocytes versus liver microsomes versus recombinant enzymes. Drug Metab. Pharmacokinet., 25, 16-27.
57. Doshi, U. and Li, A.P. (2011) Luciferin IPA-based higher throughput human hepatocyte screening assays for CYP3A4 inhibition and induction. J. Biomol. Screening, 16, 903-909.
58. Li, A.P. (2009) Evaluation of luciferin-isopropyl acetal as a CYP3A4 substrate for human hepatocytes: effects of organic solvents, cytochrome P450 (P450) inhibitors, and P450 inducers. Drug Metab. Dispos., 37, 1598-1603.
59. Li, A.P., Maurel, P., Gomez-Lechon, M.J., Cheng, L.C. and Jurima-Romet, M. (1997) Preclinical evaluation of drug-drug interaction potential: present status of the application of primary human hepatocytes in the evaluation of cytochrome P450 induction. Chem. Biol. Interact., 107, 5-16.
60. Pelletier, R.D., Lai, W.G. and Wong, Y.N. (2013) Application of a substrate cocktail approach in the assessment of cytochrome P450 induction using cultured human hepatocytes. J. Biomol. Screening, 18, 199-210.
61. Feidt, D.M., Klein, K., Hofmann, U., Riedmaier, S., Knobeloch, D., Thasler, W.E., Weiss, T.S., Schwab, M. and Zanger, U.M. (2010) Profiling induction of cytochrome p450 enzyme activity by statins using a new liquid chromatography-tandem mass spectrometry cocktail assay in human hepatocytes. Drug Metab. Dispos., 38, 1589-1597.
62. Lahoz, A., Donato, M.T., Picazo, L., Castell, J.V. and Gómez-Lechon, M.J. (2008) Assessment of cytochrome P450 induction in human hepatocytes using the cocktail strategy plus liquid chromatography tandem mass spectrometry. Drug Metab. Lett., 2, 205-209.
63. Gerin, B., Dell'Aiera, S., Richert, L., Smith, S. and Chanteux, H. (2013) Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy. Xenobiotica, 43, 320-335.
64. Halladay, J.S., Wong, S., Khojasteh, S.C. and Grepper, S. (2012) An 'all-inclusive' 96-well cytochrome P450 induction method: measuring enzyme activity, mRNA levels, protein levels, and cytotoxicity from one well using cryopreserved human hepatocytes. J. Pharmacol. Toxicol. Methods, 66, 270-275.
65. Einolf, H.J., Chen, L., Fahmi, O.A., Gibson, C.R., Obach, R.S., Shebley, M., Silva, J., Sinz, M.W., Unadkat, J.D., Zhang, L. and Zhao, P. (2014). Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mRNA induction data. Clin. Pharmacol. Ther., 95, 179-188.
66. Fahmi, O.A., Kish, M., Boldt, S. and Obach, R.S. (2010) Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes. Drug Metab. Dispos., 38, 1605-1611.
67. Rautio, J., Humphreys, J.E., Webster, L.O., Balakrishnan, A., Keogh, J.P., Kunta, J.R., Serabjit-Singh, C.J. and Polli, J.W. (2006) In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates:a recommendation for probe substrates. Drug Metab. Dispos., 34, 786-792.
68. Eberl, S., Renner, B., Neubert, A., Reisig, M., Bachmakov, I., König, J., Dörje, F., Mürdter, T.E., Ackermann, A., Dormann, H., Gassmann, K.G., Hahn, E.G., Zierhut, S., Brune, K. and Fromm, M.F. (2007) Role of p-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies. Clin. Pharmacokinet., 46, 1039-1049.
69. Ye, Z.W., Camus, S., Augustijns, P. and Annaert, P. (2010) Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes. Biopharm. Drug Dispos., 31, 178-188.
70. Keppler, D. (2005) Uptake and efflux transporters for conjugates in human hepatocytes. Methods Enzymol., 400, 531-542.
71. Matsunaga, N., Nunoya, K., Okada, M., Ogawa, M. and Tamai, I. (2013) Evaluation of hepatic disposition of paroxetine using sandwich-cultured rat and human hepatocytes. Drug Metab. Dispos., 41, 735-743.
72. Marion, T.L., Perry, C.H., St Claire, R.L., 3rd and Brouwer, K.L. (2012) Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes. Toxicol. Appl. Pharmacol., 261, 1-9.
73. Lee, J.K., Marion, T.L., Abe, K., Lim, C., Pollock, G.M. and Brouwer, K.L. (2010) Hepatobiliary disposition of troglitazone and metabolites in rat and human sandwich-cultured hepatocytes: use of Monte Carlo simulations to assess the impact of changes in biliary excretion on troglitazone sulfate accumulation. J. Pharmacol. Exp. Ther., 332, 26-34.
74. Wolf, K.K., Vora, S., Webster, L.O., Generaux, G.T., Polli, J.W. and Brouwer, K.L. (2010) Use of cassette dosing in sandwich- cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport. Toxicol. In Vitro, 24, 297-309.
75. Li, N., Bi, Y.A., Duignan, D.B. and Lai, Y. (2009) Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol. Pharmaceutics, 6, 1180-1189.
76. Reyner, E.L., Sevidal, S., West, M.A., Clouser-Roche, A., Freiwald, S., Fenner, K., Ullah, M., Lee, C.A. and Smith, B.J. (2013) In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions. Drug Metab. Dispos., 41, 1575-1583.
77. Barton, H.A., Lai, Y., Goosen, T.C., Jones, H.M., El-Kattan, A.F., Gosset, J.R., Lin, J. and Varma, M.V. (2013) Modelbased approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert. Opin. Drug Metab. Toxicol., 9, 459-472.
78. Takanohashi, T., Kubo, S., Arisaka, H., Shinkai, K. and Ubukata, K. (2012) Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug-drug interactions via these transporters. J. Pharm. Pharmacol., 64, 199-206.
79. Fahrmayr, C., Fromm, M.F. and Konig, J. (2010) Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab. Rev., 42, 380-401.
80. Kindla, J., Fromm, M.F. and König, J. (2009) In vitro evidence for the role of OATP and OCT uptake transporters in drug-drug interactions. Expert Opin. Drug Metab. Toxicol., 5, 489-500.
81. Soars, M.G., Webborn, P.J. and Riley, R.J. (2009) Impact of hepatic uptake transporters on pharmacokinetics and drugdrug interactions: use of assays and models for decision making in the pharmaceutical industry. Mol. Pharmaceutics, 6, 1662-1677.
82. Regev, A. (2013) How to avoid being surprised by hepatotoxicity at the final stages of drug development and approval. Clin. Liver Dis., 17, 749-767.
83. Giordano, C.M. and Zervos, X.B. (2013) Clinical manifestations and treatment of drug-induced hepatotoxicity. Clin. Liver Dis., 17, 565-573.
84. Hussaini, S.H. and Farrington, E.A. (2014) Idiosyncratic druginduced liver injury: an update on the 2007 overview. Expert. Opin. Drug Saf., 13, 67-81.
85. Shi, Q., Yang, X. and Mendrick, D.L. (2013) Hopes and challenges in using miRNAs as translational biomarkers for druginduced liver injury. Biomarkers Med., 7, 307-315.
86. Schomaker, S., Warner, R., Bock, J., Johnson, K., Potter, D., Van Winkle, J. and Aubrecht, J. (2013) Assessment of emerging biomarkers of liver injury in human subjects. Toxicol. Sci., 132, 276-283.
87. Persson, M., Løye, A.F., Mow, T. and Hornberg, J.J. (2013) A high content screening assay to predict human drug-induced liver injury during drug discovery. J. Pharmacol. Toxicol. Methods, 68, 302-313.
88. Pedersen, J.M., Matsson, P., Bergström, C.A., Hoogstraate, J., Norén, A., LeCluyse, E.L. and Artursson, P. (2013) Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol. Sci., 136, 328-343.
89. Li, A.P. (2002) A review of the common properties of drugs with idiosyncratic hepatotoxicity and the "multiple determinant hypothesis" for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact., 142, 7-23.
90. Amacher, D.E. (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert. Opin. Drug Metab. Toxicol., 8, 335-347.
91. Ballet, F. (2010) Back to basics for idiosyncratic drug-induced liver injury: dose and metabolism make the poison. Gastroenterol. Clin. Biol., 34, 348-350.
92. Boelsterli, U.A. (2003) Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology. Toxicol. Mech. Methods, 13, 3-20.
93. Claesson, A. and Spjuth, O. (2013) On mechanisms of reactive metabolite formation from drugs. Mini Rev. Med. Chem., 13, 720-729.
94. Saab, L., Peluso, J., Muller, C.D. and Ubeaud-Sequier, G. (2013) Implication of hepatic transporters (MDR1 and MRP2) in inflammation-associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry. Cytometry A, 83, 403-408.
95. Warner, D.J., Chen, H., Cantin, L.D., Kenna, J.G., Stahl, S., Walker, C.L. and Noeske, T. (2012) Mitigating the inhibition of human bile salt export pump by drugs: opportunities provided by physicochemical property modulation, in silico modeling, and structural modification. Drug Metab. Dispos., 40, 2332-2341.
96. Kubitz, R., Dröge, C., Stindt, J., Weissenberger, K. and Haussinger, D. (2012) The bile salt export pump (BSEP) in health and disease. Clin. Res. Hepatol. Gastroenterol., 36, 536-553.
97. Moeller, T.A., Shukla, S.J. and Xia, M. (2012) Assessment of compound hepatotoxicity using human plateable cryopreserved hepatocytes in a 1536-well-plate format. Assay Drug Dev. Technol., 10, 78-87.
98. Ning, B., Bai, M. and Shen, W. (2011) Reduced glutathione protects human hepatocytes from palmitate-mediated injury by suppressing endoplasmic reticulum stress response. Hepatogastroenterology, 58, 1670-1679.
99. O'Brien, P.J., Chan, K. and Silber, P.M. (2004) Human and animal hepatocytes in vitro with extrapolation in vivo. Chem. Biol. Interact., 150, 97-114.
100. Dvorák, Z., Kosina, P., Walterová, D., Simánek, V., Bachleda, P. and Ulrichová, J. (2003) Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybum marianum. Toxicol. Lett., 137, 201-212.
101. Prabhu, S., Fackett, A., Lloyd, S., McClellan, H.A., Terrell, C.M., Silber, P.M. and Li, A.P. (2002) Identification of glutathione conjugates of troglitazone in human hepatocytes. Chem. Biol. Interact., 142, 83-97.
102. Lloyd, S., Hayden, M.J., Sakai, Y., Fackett, A., Silber, P.M., Hewitt, N.J. and Li, A.P. (2002) Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopre served human hepatocytes from 37 donors. Chem. Biol. Interact., 142, 57-71.
103. Li, A.P., Lu, C., Brent, J.A., Pham, C., Fackett, A., Ruegg, C.E. and Silber, P.M. (1999) Cryopreserved human hepatocytes:characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem. Biol. Interact., 121, 17-35.
104. Abraham, V.C., Towne, D.L., Waring, J.F., Warrior, U. and Burns, D.J. (2008) Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans. J. Biomol. Screening, 13, 527-537.
105. O'Brien, P.J., Irwin, W., Diaz, D., Howard-Cofield, E., Krejsa, C.M., Slaughter, M.R., Gao, B., Kaludercic, N., Angeline, A., Bernardi, P., Brain, P. and Hougham, C. (2006) High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch. Toxicol., 80, 580-604.
106. Monteith, D.K. and Theiss, J.C. (1996) Comparison of tacrine-induced cytotoxicity in primary cultures of rat, mouse, monkey, dog, rabbit, and human hepatocytes. Drug Chem. Toxicol., 19, 59-70.
107. Kienhuis, A.S., van de Poll, M.C., Dejong, C.H., Gottschalk, R., van Herwijnen, M., Boorsma, A., Kleinjans, J.C., Stierum, R.H. and van Delft, J.H. (2009) A toxicogenomicsbased parallelogram approach to evaluate the relevance of coumarin-induced responses in primary human hepatocytes in vitro for humans in vivo. Toxicol. In Vitro, 23, 1163-1169.
108. Kier, L.D., Neft, R., Tang, L., Suizu, R., Cook, T., Onsurez, K., Tiegler, K., Sakai, Y., Ortiz, M., Nolan, T., Sankar, U. and Li, A.P. (2004) Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro. Mutat. Res., 549, 101-113.
109. Zhang, J.D., Berntenis, N., Roth, A. and Ebeling, M. (2014) Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity. Pharmacogenomics J., 14, 208-216.
110. Dybing, E. and Mitchell, J.R. (1977) The role of metabolic activation for drug-induced liver injuries. Acta Pharmacol. Toxicol. (Copenhagen), 41 Suppl 2, 263-272.
111. Mitchell, J.R., Nelson, S.D., Thorgeirsson, S.S., McMurtry, R.J. and Dybing, E. (1976) Metabolic activation: biochemical basis for many drug-induced liver injuries. Prog. Liver Dis., 5, 259-279.
112. Wood, A.W., Levin, W., Lu, A.Y., Yagi, H., Hernandez, O., Jerina, D.M. and Conney, A.H. (1976) Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes. J. Biol. Chem., 251, 4882-4890.
113. Guengerich, F.P., Johnson, W.W., Shimada, T., Ueng, Y.F., Yamazaki, H. and Langouët, S. (1998) Activation and detoxication of aflatoxin B1. Mutat. Res., 402, 121-128.
114. Zhao, L. and Pickering, G. (2011) Paracetamol metabolism and related genetic differences. Drug Metab. Rev., 43, 41-52.
115. Veronese, M.E. and McLean, S. (1991) Metabolism of paracetamol and phenacetin in relation to debrisoquine oxidation phenotype. Eur. J. Clin. Pharmacol., 40, 547-552.
116. Chang, T.K., Yu, L., Maurel, P. and Waxman, D.J. (1997) Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res., 57, 1946-1954.
117. Alley, M.C., Powis, G., Appel, P.L., Kooistra, K.L. and Lieber, M.M. (1984) Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines. Cancer Res., 44, 549-556.
118. Corcoran, J., Lange, A., Winter, M.J. and Tyler, C.R. (2012) Effects of pharmaceuticals on the expression of genes involved in detoxification in a carp primary hepatocyte model. Environ. Sci. Technol., 46, 6306-6314.
119. González, R., Cruz, A., Ferrín, G., López-Cillero, P., Briceño, J., Gómez, M.A., Rufián, S., Padillo, J., De la Mata, M., Marin, J.J. and Muntané, J. (2011) Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids. J. Hepatobiliary Pancreat. Sci., 18, 740-750.
120. Richter, P.A., Li, A.P., Polzin, G. and Roy, S.K. (2010) Cytotoxicity of eight cigarette smoke condensates in three test systems: comparisons between assays and condensates. Regul. Toxicol. Pharmacol., 58, 428-436.
121. Li, A.P. (2009) The use of the Integrated Discrete Multiple Organ Co-culture (IdMOC) system for the evaluation of multiple organ toxicity. Altern. Lab. Anim., 37, 377-385.
122. Li, A.P. (2007) Human-based in vitro experimental systems for the evaluation of human drug safety. Curr. Drug Saf., 2, 193-199.
123. Li, A.P. (2008) In vitro evaluation of human xenobiotic toxicity:scientific concepts and the novel integrated discrete multiple cell co-culture (IdMOC) technology. Altex, 25, 43-49.
124. Li, A.P., Bode, C. and Sakai, Y. (2004) A novel in vitro system, the integrated discrete multiple organ cell culture (IdMOC) system, for the evaluation of human drug toxicity:comparative cytotoxicity of tamoxifen towards normal human cells from five major organs and MCF-7 adenocarcinoma breast cancer cells. Chem. Biol. Interact., 150, 129-136.
125. Daniels, J.S., Lai, Y., South, S., Chiang, P.C., Walker, D., Feng, B., Mireles, R., Whiteley, L.O., McKenzie, J.W., Stevens, J., Mourey, R., Anderson, D. and Davis li, J.W. (2013) Inhibition of Hepatobiliary Transporters by A Novel Kinase Inhibitor Contributes to Hepatotoxicity in Beagle Dogs. Drug Metab. Lett., 7, 15-22.
126. Amacher, D.E. (2010) The discovery and development of proteomic safety biomarkers for the detection of druginduced liver toxicity. Toxicol. Appl. Pharmacol., 245, 134-142.
127. Beger, R.D., Sun, J. and Schnackenberg, L.K. (2010) Metabolomics approaches for discovering biomarkers of druginduced hepatotoxicity and nephrotoxicity. Toxicol Appl Pharmacol 243, 154-166.