1932

Abstract

Most of what we know about a drug prior to human clinical studies is derived from animal testing. Because animals and humans have substantial differences in their physiology and in their drug metabolism pathways, we do not know very much about the pharmacokinetic and pharmacodynamic behavior of a drug in humans until after it is administered to many people. Hence, drug-induced liver injury has become a significant public health problem, and we have a very inefficient drug development process with a high failure rate. Because the human liver is at the heart of these problems, chimeric mice with humanized livers could be used to address these issues. We examine recent evidence indicating that drug testing in chimeric mice could provide better information about a drug's metabolism, disposition, and toxicity (i.e., its “behavior”) in humans and could aid in developing personalized medicine strategies, which would improve drug efficacy and safety.

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2016-01-06
2024-12-02
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Literature Cited

  1. Harding A. 1.  2004. More compounds failing Phase I. The Scientist Sept. 13. http://www.the-scientist.com/?articles.view/articleNo/15910/title/More-Compounds-Failing-Phase-I/ [Google Scholar]
  2. Peltz G. 2.  2013. Can ‘humanized’ mice improve drug development in the 21st century?. Trends Pharmacol. Sci. 34:255–60 [Google Scholar]
  3. Williams JA, Andersson T, Andersson TB, Blanchard R, Behm MO. 3.  et al. 2008. PhRMA white paper on ADME pharmacogenomics. J. Clin. Pharmacol. 48:849–89 [Google Scholar]
  4. Anderson S, Luffer-Atlas D, Knadler MP. 4.  2009. Predicting circulating human metabolites: How good are we?. Chem. Res. Toxicol. 22:243–56 [Google Scholar]
  5. Walker D, Brady J, Dalvie D, Davis J, Dowty M. 5.  et al. 2009. A holistic strategy for characterizing the safety of metabolites through drug discovery and development. Chem. Res. Toxicol. 22:1653–62 [Google Scholar]
  6. Leclercq L, Cuyckens F, Mannens GS, de Vries R, Timmerman P, Evans DC. 6.  2009. Which human metabolites have we MIST? Retrospective analysis, practical aspects, and perspectives for metabolite identification and quantification in pharmaceutical development. Chem. Res. Toxicol. 22:280–93 [Google Scholar]
  7. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ. 7.  et al. 2002. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 137:947–54 [Google Scholar]
  8. Watkins PB, Seeff LB. 8.  2006. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 43:618–31 [Google Scholar]
  9. Olson H, Betton G, Robinson D, Thomas K, Monro A. 9.  et al. 2000. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32:56–67 [Google Scholar]
  10. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM. 10.  et al. 1995. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med. 333:1099–105 [Google Scholar]
  11. Manning FJ, Swartz MN. 11.  1995. Review of the Fialuridine (FIAU) Clinical Trials Washington, DC: Natl. Acad. [Google Scholar]
  12. Regev A. 12.  2014. Drug-induced liver injury and drug development: industry perspective. Semin. Liver Dis. 34:227–39 [Google Scholar]
  13. Avigan MI. 13.  2014. DILI and drug development: a regulatory perspective. Semin. Liver Dis. 34:215–26 [Google Scholar]
  14. Sandgren EP, Palmiter RD, Heckel JL, Daugherty CC, Brinster RL, Degen JL. 14.  1991. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 66:245–56 [Google Scholar]
  15. Tateno C, Yoshizane Y, Saito N, Kataoka M, Utoh R. 15.  et al. 2004. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am. J. Pathol. 165:901–12 [Google Scholar]
  16. Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M. 16.  et al. 2007. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat. Biotechnol. 25:903–10 [Google Scholar]
  17. Cederbaum SD, Scott CR, Wilcox WR. 17.  1997. Amino acid metabolism. Principles and Practice of Medical Genetics 2 DL Rimoin, JM Connor, RE Pyeritz 1872–75 New York: Churchill Livingstone [Google Scholar]
  18. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M. 18.  et al. 2002. NOD/SCID/γnullc mouse: an excellent recipient mouse model for engraftment of human cells. Blood 1003175–82 [Google Scholar]
  19. Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M. 19.  et al. 2011. The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional. Biochem. Biophys. Res. Commun. 405:405–10 [Google Scholar]
  20. Chen AA, Thomas DK, Ong LL, Schwartz RE, Golub TR, Bhatia SN. 20.  2011. Humanized mice with ectopic artificial liver tissues. PNAS 108:11842–47 [Google Scholar]
  21. Katoh M, Yokoi T. 21.  2007. Application of chimeric mice with humanized liver for predictive ADME. Drug Metab. Rev. 39:145–57 [Google Scholar]
  22. Katoh M, Sawada T, Soeno Y, Nakajima M, Tateno C. 22.  et al. 2007. In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J. Pharm. Sci. 96:428–37 [Google Scholar]
  23. Lootens L, Van Eenoo P, Meuleman P, Leroux-Roels G, Delbeke FT. 23.  2009. The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione. Drug Metab. Dispos. 37:2367–74 [Google Scholar]
  24. Pozo OJ, Van Eenoo P, Deventer K, Lootens L, Grimalt S. 24.  et al. 2009. Detection and structural investigation of metabolites of stanozolol in human urine by liquid chromatography tandem mass spectrometry. Steroids 74:837–52 [Google Scholar]
  25. Kamimura H, Nakada N, Suzuki K, Mera A, Souda K. 25.  et al. 2010. Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites. Drug Metab. Pharmacokinet. 25:223–35 [Google Scholar]
  26. Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y. 26.  et al. 2012. Prediction of in vivo hepatic clearance and half-life of drug candidates in human using chimeric mice with humanized liver. Drug Metab. Dispos. 40:322–28 [Google Scholar]
  27. Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y. 27.  et al. 2012. Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes. Drug Metab. Dispos. 40:2267–72 [Google Scholar]
  28. De Serres M, Bowers G, Boyle G, Beaumont C, Castellino S. 28.  et al. 2011. Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism. Xenobiotica 41:464–75 [Google Scholar]
  29. Nishimura T, Hu Y, Wu M, Pham E, Suemizu H. 29.  et al. 2013. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J. Pharmacol. Exp. Ther. 344:388–98 [Google Scholar]
  30. Smith DA, Obach RS. 30.  2009. Metabolites in safety testing (MIST): considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chem. Res. Toxicol. 22:267–79 [Google Scholar]
  31. Guengerich FP, MacDonald JS. 31.  2007. Applying mechanisms of chemical toxicity to predict drug safety. Chem. Res. Toxicol. 20:344–69 [Google Scholar]
  32. Okumura H, Katoh M, Sawada T, Nakajima M, Soeno Y. 32.  et al. 2007. Humanization of excretory pathway in chimeric mice with humanized liver. Toxicol. Sci. 97:533–38 [Google Scholar]
  33. Xu D, Wu M, Nishimura S, Nishimura T, Michie SA. 33.  et al. 2015. Chimeric TK–NOG mice: a predictive model for cholestatic human liver toxicity. J. Pharm. Exp. Ther. 352:274–80 [Google Scholar]
  34. van Giersbergen PL, Treiber A, Schneiter R, Dietrich H, Dingemanse J. 34.  2007. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin. Pharmacol. Ther. 81:414–19 [Google Scholar]
  35. Treiber A, Schneiter R, Häusler S, Stieger B. 35.  2007. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab. Dispos. 35:1400–7 [Google Scholar]
  36. Xu D, Nishimura T, Nishimura S, Zhang H, Zheng M. 36.  et al. 2014. Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing. PLOS Med. 11:e1001628 [Google Scholar]
  37. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T. 37.  et al. 2013. Sofosbuvir for previously untreated chronic hepatitis C infection. N. Engl. J. Med. 368:1878–87 [Google Scholar]
  38. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM. 38.  et al. 2002. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346:896–903 [Google Scholar]
  39. Fattinger K, Funk C, Pantze M, Weber C, Reichen J. 39.  et al. 2001. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69:223–31 [Google Scholar]
  40. Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. 40.  2007. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur. Respir. J. 30:338–44 [Google Scholar]
  41. Trusheim MR, Burgess B, Hu SX, Long T, Averbuch SD. 41.  et al. 2011. Quantifying factors for the success of stratified medicine. Nat. Rev. Drug Discov. 10:817–33 [Google Scholar]
  42. Guo Y, Shafer S, Weller P, Usuka J, Peltz G. 42.  2005. Pharmacogenomics and drug development. Pharmacogenomics 6:857–64 [Google Scholar]
  43. Weinshilboum R, Wang L. 43.  2004. Pharmacogenomics: bench to bedside. Nat. Rev. Drug Discov. 3:739–48 [Google Scholar]
  44. Hu Y, Wu M, Nishimura T, Zheng M, Peltz G. 44.  2013. Human pharmacogenetic analysis in chimeric mice with ‘humanized livers.’. Pharmacogenet. Genomics 23:78–83 [Google Scholar]
  45. Zhou HH. 45.  2001. CYP2C19 genotype determines enzyme activity and inducibility of S-mephenytoin hydroxylase. Clin. Chim. Acta 313:203–8 [Google Scholar]
  46. Desta Z, Zhao X, Shin JG, Flockhart DA. 46.  2002. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin. Pharmacokinet. 41:913–58 [Google Scholar]
  47. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS. 47.  et al. 2011. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin. Pharmacol. Ther. 90:328–32 [Google Scholar]
  48. Pirmohamed M, Park BK. 48.  2003. Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology 192:23–32 [Google Scholar]
  49. Lee CR, Goldstein JA, Pieper JA. 49.  2002. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–63 [Google Scholar]
  50. Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, Llerena A. 50.  2003. CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur. J. Clin. Pharmacol. 59:221–25 [Google Scholar]
  51. Xu D, Nishimura T, Zheng M, Woo M, Su H. 51.  et al. 2014. Enabling autologous human liver regeneration with differentiated adipocyte stem cells. Cell Transplant. 23:1573–84 [Google Scholar]
  52. Bissig K-D, Wieland SF, Tran P, Isogawa M, Le TT. 52.  et al. 2010. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J. Clin. Investig. 120:650–53 [Google Scholar]
  53. Ohara E, Hiraga N, Imamura M, Iwao E, Kamiya N. 53.  et al. 2011. Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice. J. Hepatol. 54:872–78 [Google Scholar]
  54. Zhang L, Reynolds KS, Zhao P, Huang SM. 54.  2010. Drug interactions evaluation: an integrated part of risk assessment of therapeutics. Toxicol. Appl. Pharmacol. 243:134–45 [Google Scholar]
  55. Bode C. 55.  2010. The nasty surprise of a complex drug-drug interaction. Drug Discov. Today 15:391–95 [Google Scholar]
  56. van Herwaarden AE, Wagenaar E, van der Kruijssen CMM, van Waterschoot RAB, Smit JW. 56.  et al. 2007. Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. J. Clin. Investig. 117:3583–92 [Google Scholar]
  57. van Waterschoot RAB, van Herwaarden AE, Lagas JS, Sparidans RW, Wagenaar E. 57.  et al. 2008. Midazolam metabolism in cytochrome P450 3A knockout mice can be attributed to up-regulated CYP2C enzymes. Mol. Pharmacol. 73:1029–36 [Google Scholar]
  58. Nelson DR, Zeldin DC, Hoffman SMG, Maltais LJ, Wain HM, Nebert DW. 58.  2004. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14:1–18 [Google Scholar]
  59. Guo YY, Weller PF, Farrell E, Cheung P, Fitch B. 59.  et al. 2006. In silico pharmacogenetics: warfarin metabolism. Nat. Biotechnol. 24:531–36 [Google Scholar]
  60. Hersman EM, Bumpus NN. 60.  2014. A targeted proteomics approach for profiling murine cytochrome P450 expression. J. Pharmacol. Exp. Ther. 349:221–28 [Google Scholar]
  61. Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ. 61.  et al. 2014. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346:1480–86 [Google Scholar]
  62. Nagamoto Y, Takayama K, Tashiro K, Tateno C, Sakurai F. 62.  et al. 2014. Efficient engraftment of human iPS cell-derived hepatocyte-like cells in uPA/SCID mice by overexpression of FNK, a Bcl-xL mutant gene. Cell Transplant. 24:1127–38 [Google Scholar]
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