Biomarkers and human hepatocytes

Biomarkers in Medicine

Volumn 8, Issue 2, 2014, Pages 173-183

  Li, Albert P ^a  

^a In Vitro ADMET Laboratories LLC   (United States)

Author keywords

biomarkers; drug development; drug metabolism; drug toxicity; drug drug interactions; human hepatocytes

Indexed keywords

BIOLOGICAL MARKERS; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; DRUG-INDUCED LIVER INJURY; HUMANS; LIVER; METABOLOME; P-GLYCOPROTEIN; PHARMACEUTICAL PREPARATIONS; PROTEIN ISOFORMS;

EID: 84894375635     PISSN: 17520363     EISSN: 17520371     Source Type: Journal    
DOI: 10.2217/bmm.13.155     Document Type: Review

References (142)

1. Li AP. Accurate prediction of human drug toxicity: a major challenge in drug development. Chem. Biol. Interact. 150(1), 3-7 (2004).
2. Li AP. Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol. Biol. 640, 281-294 (2010).
3. Baillie TT, Rettie AE. Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism. Drug Metab. Pharmacokinet. 26(1), 15-29 (2011).
4. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3(8), 711-715 (2004).
5. Montastruc F, Sommet A, Bondon-Guitton E et al. 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(5), 767-775 (2012).
6. Takarabe M, Shigemizu D, Kotera M, Goto S, Kanehisa M. Network-based analysis and characterization of adverse drug-drug interactions. J. Chem. Inf. Model. 51(11), 2977-2985 (2011).
7. Assis DD, Navarro VJ. Human drug hepatotoxicity: a contemporary clinical perspective. Expert Opin. Drug Metab. Toxicol. 5(5), 463-473 (2009).
8. Kaplowitz N. Avoiding idiosyncratic DILI: two is better than one. Hepatology 58(1), 15-17 (2013).
9. Stephens C, Lucena MI, Andrade RJ. Genetic variations in drug-induced liver injury (DILI): resolving the puzzle. Front. Genet. 3, 253 (2012).
10. Hawkins MM, Lewis JH. Latest advances in predicting DILI in human subjects: focus on biomarkers. Expert Opin. Drug Metab. Toxicol. 8(12), 1521-1530 (2012).
11. Li AP. Human hepatocytes as an effective alternative experimental system for the evaluation of human drug properties: general concepts and assay procedures. ALTEX 25(1), 33-42 (2008).
12. Li AP. Human hepatocytes: isolation, cryopreservation and applications in drug development. Chem. Biol. Interact. 168(1), 16-29 (2007).
13. Gmez-Lechn MJ, Lahoz A, Jimnez N, Vicente Castell J, Donato MT. Cryopreservation of rat, dog and human hepatocytes: influence of preculture and cryoprotectants on recovery, cytochrome P450 activities and induction upon thawing. Xenobiotica 36(6), 457-472 (2006).
14. Terry C, Mitry RR, Lehec SC et al. The effects of cryopreservation on human hepatocytes obtained from different sources of liver tissue. Cell Transplant. 14(8), 585-594 (2005).
15. De Bruyn T, Ye ZW, Peeters A et al. Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. Eur. J. Pharm. Sci. 43(4), 297-307 (2011).
16. Kimoto E, Yoshida K, Balogh LM et al. Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. Mol. Pharm. 9 (12), 3535-3542 (2012).
17. Maeda K, Kambara M, Tian Y, Hofmann AF, Sugiyama Y. Uptake of ursodeoxycholate and its conjugates by human hepatocytes: role of Na(+)-taurocholate cotransporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8). Mol. Pharm. 3(1), 70-77 (2006).
18. Shitara Y, Li AP, Kato Y et al. Function of uptake transporters for taurocholate and estradiol 17beta-d-glucuronide in cryopreserved human hepatocytes. Drug Metab. Pharmacokinet. 18(1), 33-41 (2003).
19. Li M, Yuan H, Li N et al. 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(1), 66-73 (2009).
20. Li M, Zhang Y, HuaF, Lai Y. Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human. Eur. J. Pharm. Sci. 35(1-2), 114-126 (2008).
21. Bi YA, Kazolias D, Duignan DB. Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab. Dispos. 34(9), 1658-1665 (2006).
22. Chen Y, Liu L, Monshouwer M, Fretland AJ. Determination of time-dependent inactivation of CYP3A4 in cryopreserved human hepatocytes and assessment of human drug-drug interactions. Drug Metab. Dispos. 39(11), 2085-2092 (2011).
23. Xu L, Chen Y, Pan Y, Skiles GL, Shou M. Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab. Dispos. 37(12), 2330-2339 (2009).
24. Li AP, Doshi U. Higher throughput human hepatocyte assays for the evaluation of time-dependent inhibition of CYP3A4. Drug Metab. Lett. 5(3), 183-191 (2011).
25. McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ. Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab. Dispos. 34(8), 1291-1300 (2006).
26. Zhao P, Kunze KL, Lee CA. Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab. Dispos. 33(6), 853-861 (2005).
27. Li AP. 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: proof-of-concept study with aflatoxin B1. Chem. Biol. Interact. 179(1), 4-8 (2009).
28. Li AP, Uzgare A, LaForge YS. 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), 1-8 (2012).
29. Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am. J. Cardiol. 83(5A), 21C-28C (1999).
30. Li AP, Kaminski DL, Rasmussen A. Substrates of human hepatic cytochrome P450 3A4. Toxicology 104(1-3), 1-8 (1995).
31. Zimmermann M, Duruz H, Guinand O et al. Torsades de Pointes after treatment with terfenadine and ketoconazole. Eur. Heart J. 13(7), 1002-1003 (1992).
32. Flockhart DD. Drug interactions, cardiac toxicity, and terfenadine: from bench to clinic? J. Clin. Psychopharmacol. 16(2), 101-103 (1996).
33. Ishizaki T. Strategic proposals to avoid drug interactions during drug development: a lesson from a terfenadine-related drug interaction. J. Toxicol. Sci. 21(5), 301-303 (1996).
34. Terrien MH, Rahm F, Fellrath JM, Spertini F. Comparison of the effects of terfenadine with fexofenadine on nasal provocation tests with allergen. J. Allergy Clin. Immunol. 103(6), 1025-1030 (1999).
35. Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions. II. Arch. Intern. Med. 152(4), 711-716 (1992).
36. Holdiness MM. Rifampin drug interactions. Arch. Intern. Med. 147(10), 1856 (1987).
37. Baciewicz AM, Self TH, Bekemeyer WB. Update on rifampin drug interactions. Arch. Intern. Med. 147(3), 565-568 (1987).
38. Baciewicz AA, Self TH. Rifampin drug interactions. Arch. Intern. Med. 144(8), 1667-1671 (1984).
39. Offermann G, Keller F, Molzahn M. Low cyclosporin A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment. Am. J. Nephrol. 5(5), 385-387 (1985).
40. Muller F, Fromm MF. Transporter-mediated drug-drug interactions. Pharmacogenomics 12(7), 1017-1037 (2011).
41. Zhang L, Huang SM, Lesko LJ. Transporter-mediated drug-drug interactions. Clin. Pharmacol. Ther. 89(4), 481-484 (2011).
42. Zhang L, Huang SM, Lesko LJ. Evaluation of drug transporter interactions in drug discovery and development. Comb. Chem. High Throughput Screen. 13(2), 112-134 (2010).
43. Tsuji A. Transporter-mediated drug interactions. Drug Metab. Pharmacokinet. 17(4), 253-274 (2002).
44. Maeda K, Sugiyama Y. Transporter biology in drug approval: regulatory aspects. Mol. Aspects Med. 34(2-3), 711-718 (2013).
45. Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM. Highlights from the International Transporter Consortium second workshop. Clin. Pharmacol. Ther. 92(5), 553-556 (2012).
46. Zhang L, Zhang YD, Strong JM, Reynolds KS, Huang SM. A regulatory viewpoint on transporter-based drug interactions. Xenobiotica 38(7-8), 709-724 (2008).
47. Schmitt C, Kaeser B, Riek M, Bech N, Kreuzer C. Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe. Int. J. Clin. Pharmacol. Ther. 48(3), 192-199 (2010).
48. Andersen V, Pedersen N, Larsen NE, Sonne J, Larsen S. Intestinal first pass metabolism of midazolam in liver cirrhosis - effect of grapefruit juice. Br. J. Clin. Pharmacol. 54, 120-124 (2002).
49. Dingemanse J, van Giersbergen PL, Patat A, Nilsson PN. Mutual pharmacokinetic interactions between bosentan and lopinavir/ ritonavir in healthy participants. Antivir. Ther. 15(2), 157-163 (2010).
50. Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y. et al. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J. Pharmacol. Exp. Ther. 304(2), 610-616 (2003).
51. Shitara Y, Hirano M, Adachi Y, Itoh T, Sato H, Sugiyama Y. In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats. Drug Metab. Dispos. 32(12), 1468-1475 (2004).
52. Renders L, Czock D, Schcklmann H, Kunzendorf U. Determination of the pharmacokinetics of cerivastatin when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of the relevant literature. Int. J. Clin. Pharmacol. Ther. 41(11), 499-503 (2003).
53. Mora C, Rodrguez ML, Navarro JF. Cerivastatin-induced rhabdomyolysis in a renal transplant on cyclosporin. Transplantation 72(3), 551 (2001).
54. Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampins inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin. Pharmacol. Ther. 85(1), 78-85 (2009).
55. Tsuda M, Terada T, Ueba M et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J. Pharmacol. Exp. Ther. 329(1), 185-191 (2009).
56. Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet. Genomics 18(7), 637-645 (2008).
57. Landersdorfer CB, Kirkpatrick CM, Kinzig M et al. Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid. Br. J. Clin. Pharmacol. 69(2), 167-178 (2010).
58. Landersdorfer CB, Kirkpatrick CM, Kinzig M et al. Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid. Antimicrob. Agents Chemother. 53(9), 3902-3907 (2009).
59. Lee JI, Zhang L, Men AY, Kenna LA, Huang SM. CYP-mediated therapeutic protein-drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin. Pharmacokinet. 49(5), 295-310 (2010).
60. Zhang L, Zhang Y, Huang SM. Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol. Pharm. 6(6), 1766-1774 (2009).
61. Mller HJ, Gundert-Remy U. The regulatory view on drug-drug interactions. Int. J. Clin. Pharmacol. Ther. 32(6), 269-273 (1994).
62. Darnell M, Ulvestad M, Ellis E, Weidolf L, Andersson TB. 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(1), 134-144 (2012).
63. Gmez-Lechn MJ, Donato MT, Castell JV, Jover R. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr. Drug Metab. 5(5), 443-462 (2004).
64. Hong H, Su H, Ma L et al. 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(9), 1658-1667 (2011).
65. Khojasteh SC, Prabhu S, Kenny JR, Halladay JS, Lu AY. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet. 36(1), 1-16 (2011).
66. Parkinson A, Kazmi F, Buckley DB, Yerino P, Ogilvie BW, Paris BL. 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(1), 16-27 (2010).
67. Doshi U, Li AP. Luciferin IPA-based higher throughput human hepatocyte screening assays for CYP3A4 inhibition and induction. J. Biomol. Screen. 16(8), 903-909 (2011).
68. Li AP. 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(8), 1598-1603 (2009).
69. Li AP, Maurel P, Gomez-Lechon MJ, Cheng LC, Jurima-Romet M. 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(1-2), 5-16 (1997).
70. Pelletier RD, Lai WG, Wong YN. Application of a substrate cocktail approach in the assessment of cytochrome P450 induction using cultured human hepatocytes. J. Biomol. Screen. 18(2), 199-210 (2013).
71. Feidt DM, Klein K, Hofmann U et al. 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(9), 1589-1597 (2010).
72. Lahoz A, Donato MT, Picazo L, Castell JV, Gmez-Lechn MJ. Assessment of cytochrome P450 induction in human hepatocytes using the cocktail strategy plus liquid chromatography tandem mass spectrometry. Drug Metab. Lett. 2(3), 205-209 (2008).
73. Gerin B, DellAiera S, Richert L, Smith S, Chanteux H. 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(4), 320-335 (2013).
74. Halladay JS, Wong S, Khojasteh SC, Grepper S. 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(3), 270-275 (2012).
75. Einolf H, Chen L, Fahmi O et al. Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mRNA induction data. Clin. Pharmacol. Ther. doi:10.1038/ clpt.2013.170 (2013) (Epub ahead of print).
76. Fahmi OA, Kish M, Boldt S, Obach RS. 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(9), 1605-1611 (2010).
77. Rautio J, Humphreys JE, Webster LO et al. 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(5), 786-792 (2006).
78. Eberl S, Renner B, Neubert A et al. Role of P-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies. Clin. Pharmacokinet. 46(12), 1039-1049 (2007).
79. Ye ZW, Camus S, Augustijns P, Annaert P. Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes. Biopharm. Drug Dispos. 31(2-3), 178-188 (2010).
80. Keppler D. Uptake and efflux transporters for conjugates in human hepatocytes. Methods Enzymol. 400, 531-542 (2005).
81. Matsunaga N, Nunoya K, Okada M, Ogawa M, Tamai I. Evaluation of hepatic disposition of paroxetine using sandwich-cultured rat and human hepatocytes. Drug Metab. Dispos. 41(4), 735-743 (2013).
82. Marion TL, Perry CH, St Claire RL 3rd, Brouwer KL. Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes. Toxicol. Appl. Pharmacol. 261(1), 1-9 (2012).
83. Lee JK, Marion TL, Abe K, Lim C, Pollock GM, Brouwer KL. 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(1), 26-34 (2010).
84. Wolf KK, Vora S, Webster LO, Generaux GT, Polli JW, Brouwer KL. Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport. Toxicol. In Vitro 24(1), 297-309 (2010).
85. Li N, Bi YA, Duignan DB, Lai Y. Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol. Pharm. 6(4), 1180-1189 (2009).
86. Reyner EL, Sevidal S, West MA et al. In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions. Drug Metab. Dispos. 41(8), 1575-1583 (2013).
87. Barton HA, Lai Y, Goosen TC et al. Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert Opin. Drug Metab. Toxicol. 9(4), 459-472 (2013).
88. Takanohashi T, Kubo S, Arisaka H, Shinkai K, Ubukata K. 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(2), 199-206 (2012).
89. Fahrmayr C, Fromm MF, Knig J. Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab. Rev. 42(3), 380-401 (2010).
90. Soars MG, Webborn PJ, Riley RJ. In vitro evidence for the role of OATP and OCT uptake transporters in drug-drug interactions. Expert Opin. Drug Metab. Toxicol. 5(5), 489-500 (2009).
91. Soars MG, Webborn PJ, Riley RJ. Impact of hepatic uptake transporters on pharmacokinetics and drug-drug interactions: use of assays and models for decision making in the pharmaceutical industry. Mol. Pharm. 6(6), 1662-1677 (2009).
92. Regev A. How to avoid being surprised by hepatotoxicity at the final stages of drug development and approval. Clin. Liver Dis. 17(4), 749-767 (2013).
93. Giordano CC, Zervos XB. Clinical manifestations and treatment of drug-induced hepatotoxicity. Clin. Liver Dis. 17(4), 565-573 (2013).
94. Hussaini SS, Farrington EA. Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin. Drug Saf. 13(1), 67-81 (2014).
95. Shi Q, Yang X, Mendrick DL. Hopes and challenges in using miRNAs as translational biomarkers for drug-induced liver injury. Biomarkers Med. 7(2), 307-315 (2013).
96. Schomaker S, Warner R, Bock J et al. Assessment of emerging biomarkers of liver injury in human subjects. Toxicol. Sci. 132(2), 276-283 (2013).
97. Persson M, Lye AF, Mow T, Hornberg JJ. A high content screening assay to predict human drug-induced liver injury during drug discovery. J. Pharmacol. Toxicol. Methods 68(3), 302-313 (2013).
98. Pedersen JM, Matsson P, Bergstrm CA et al. Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol. Sci. 136(2), 328-343 (2013).
99. Li AP. 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(1-2), 7-23 (2002).
100. Amacher DD. The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 8(3), 335-347 (2012).
101. Ballet F. Back to basics for idiosyncratic drug-induced liver injury: dose and metabolism make the poison. Gastroenterol. Clin. Biol. 34(6-7), 348-350 (2010).
102. Boelsterli UU. Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology. Toxicol. Mech. Methods 13(1), 3-20 (2003).
103. Claesson A, Spjuth O. On mechanisms of reactive metabolite formation from drugs. Mini Rev. Med. Chem. 13(5), 720-729 (2013).
104. Saab L, Peluso J, Muller CD, Ubeaud- Sequier G. Implication of hepatic transporters (MDR1 and MRP2) in inflammation-Associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry. Cytometry A 83(4), 403-408 (2013).
105. Warner DJ, Chen H, Cantin LD et al. 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(12), 2332-2341 (2012).
106. Kubitz R, Drge C, Stindt J, Weissenberger K, Hussinger D. The bile salt export pump (BSEP) in health and disease. Clin. Res. Hepatol. Gastroenterol. 36(6), 536-553 (2012).
107. Moeller TA, Shukla SJ, Xia M. Assessment of compound hepatotoxicity using human plateable cryopreserved hepatocytes in a 1536-well-plate format. Assay Drug Dev. Technol. 10(1), 78-87 (2012).
108. Ning B, Bai M, Shen W. Reduced glutathione protects human hepatocytes from palmitate-mediated injury by suppressing endoplasmic reticulum stress response. Hepatogastroenterology 58(110-111), 1670-1679 (2011).
109. OBrien PJ, Chan K, Silber PM. Human and animal hepatocytes in vitro with extrapolation in vivo. Chem. Biol. Interact. 150(1), 97-114 (2004).
110. Dvork Z, Kosina P, Walterov D, Simnek V, Bachleda P, Ulrichov J. 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(3), 201-212 (2003).
111. Prabhu S, Fackett A, Lloyd S et al. Identification of glutathione conjugates of troglitazone in human hepatocytes. Chem. Biol. Interact. 142(1-2), 83-97 (2002).
112. Lloyd S, Hayden MJ, Sakai Y et al. Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors. Chem. Biol. Interact. 142(1-2), 57-71 (2002).
113. Li AP, Lu C, Brent JA et al. 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(1), 17-35 (1999).
114. Abraham VC, Towne DL, Waring JF, Warrior U, Burns DJ. Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans. J. Biomol. Screen. 13(6), 527-537 (2008).
115. OBrien PJ, Irwin W, Diaz D et al. 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(9), 580-604 (2006).
116. Monteith DK, Theiss JC. Comparison of tacrine-induced cytotoxicity in primary cultures of rat, mouse, monkey, dog, rabbit, and human hepatocytes. Drug Chem. Toxicol. 19(1-2), 59-70 (1996).
117. Kienhuis AS, van de Poll MC, Dejong CH et al. A toxicogenomics-based parallelogram approach to evaluate the relevance of coumarin-induced responses in primary human hepatocytes in vitro for humans in vivo. Toxicol. In Vitro 23(6), 1163-1169 (2009).
118. Kier LD, Neft R, Tang L et al. 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(1-2), 101-113 (2004).
119. Zhang JD, Berntenis N, Roth A, Ebeling M. Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity. Pharmacogenomics J. doi:10.1038/tpj.2013.39 (2013) (Epub ahead of print).
120. Dybing E, Mitchell JR. The role of metabolic activation for drug-induced liver injuries. Acta Pharmacol. Toxicol. (Copenh.) 41(Suppl. 2), 263-272 (1977).
121. Mitchell JR, Nelson SD, Thorgeirsson SS, McMurtry RJ, Dybing E. Metabolic activation: biochemical basis for many drug-induced liver injuries. Prog. Liver Dis. 5, 259-279 (1976).
122. Wood AW, Levin W, Lu AY et al. Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes. J. Biol. Chem. 251(16), 4882-4890 (1976).
123. Guengerich FP, Johnson WW, Shimada T, Ueng YF, Yamazaki H, Langout S. Activation and detoxication of aflatoxin B1. Mutat. Res. 402(1-2), 121-128 (1998).
124. Zhao L, Pickering G. Paracetamol metabolism and related genetic differences. Drug Metab. Rev. 43(1), 41-52 (2011).
125. Veronese MM, McLean S. Metabolism of paracetamol and phenacetin in relation to debrisoquine oxidation phenotype. Eur. J. Clin. Pharmacol. 40(6), 547-552 (1991).
126. Chang TK, Yu L, Maurel P, Waxman DJ. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 57(10), 1946-1954 (1997).
127. Alley MC, Powis G, Appel PL, Kooistra KL, Lieber MM. Activation and inactivation of cancer chemotherapeutic agents by rat hepatocytes cocultured with human tumor cell lines. Cancer Res. 44(2), 549-556 (1984).
128. Corcoran J, Lange A, Winter MJ, Tyler CR. Effects of pharmaceuticals on the expression of genes involved in detoxification in a carp primary hepatocyte model. Environ. Sci. Technol. 46(11), 6306-6314 (2012).
129. Gonzalez R, Cruz A, Ferrn G et al. 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(5), 740-750 (2011).
130. Richter PA, Li AP, Polzin G, Roy SK. Cytotoxicity of eight cigarette smoke condensates in three test systems: comparisons between assays and condensates. Regul. Toxicol. Pharmacol. 58(3), 428-436 (2010).
131. Li AP. The use of the Integrated discrete Multiple Organ Co-culture (IdMOC) system for the evaluation of multiple organ toxicity. Altern. Lab. Anim. 37(4), 377-385 (2009).
132. Li AP. Human-based in vitro experimental systems for the evaluation of human drug safety. Curr. Drug Saf. 2(3), 193-199 (2007).
133. Li AP. In vitro evaluation of human xenobiotic toxicity: scientific concepts and the novel Integrated discrete Multiple cell Co-culture (IdMOC) technology. ALTEX 25(1), 43-49 (2008).
134. Li AP, Bode C, Sakai Y. 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(1), 129-136 (2004).
135. Daniels JS, Lai Y, South S et al. Inhibition of hepatobiliary transporters by a novel kinase inhibitor contributes to hepatotoxicity in beagle dogs. Drug Metab. Lett. 7(1), 15-22 (2013).
136. Amacher DD. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol. Appl. Pharmacol. 245(1), 134-142 (2010).
137. Beger RD, Sun J, Schnackenberg LK. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity. Toxicol. Appl. Pharmacol. 243(2), 154-166 (2010).
138. Li AP, Hartman NR, Lu C, Collins JM, Strong JM. Effects of cytochrome P450 inducers on 17alpha-ethinyloestradiol (EE2) conjugation by primary human hepatocytes. Br. J. Clin. Pharmacol. 48(5), 733-742 (1999).
139. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)- mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J. Pharmacol. Exp. Ther. 311(1), 228-236 (2004).
140. Varma MV, Lai Y, Kimoto E, Goosen TC, El-Kattan AF, Kumar V. Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm. Res. 30(4), 1188-1199 (2013).
141. Pillai VC, Venkataramanan R, Parise RA et al. Ritonavir and efavirenz significantly alter the metabolism of erlotinib - an observation in primary cultures of human hepatocytes that is relevant to HIV patients with cancer. Drug Metab. Dispos. 41(10), 1843-1851 (2013).
142. Bi YA, Kimoto E, Sevidal S et al. In vitro evaluation of hepatic transporter-mediated clinical drug-drug interactions: hepatocyte model optimization and retrospective investigation. Drug Metab. Dispos. 40(6), 1085-1092 (2012).