Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 46, 2016 - Issue 6
735
Views
14
CrossRef citations to date
0
Altmetric
Topics in Xenobiochemistry (Review)

Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound

&
Pages 557-569 | Received 17 Jul 2015, Accepted 02 Sep 2015, Published online: 07 Oct 2015

References

  • Adachi K, Suemizu H, Murayama N, et al. (2015). Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling. Environ Toxicol Pharmacol 39:1067–73
  • Akabane T, Tanaka K, Irie M, et al. (2011). Case report of extensive metabolism by aldehyde oxidase in humans: pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans. Xenobiotica 41:372–84
  • Anderson S, Luffer-Atlas D, Knadler MP. (2009). Predicting circulating human metabolites: how good are we? Chem Res Toxicol 22:243–56
  • Azuma H, Paulk N, Ranade A, et al. (2007). Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25:903–10
  • Bacolod MD, Nguyen K, Zou Z, et al. (2011). Utilization of chimeric mice with humanized liver as a useful model for predicting human pharmacokinetics (PK) of a drug candidate with major aldehyde oxidase (AO) metabolism.The 17th North American Regional ISSX P27
  • Bateman TJ, Reddy VG, Kakuni M, et al. (2014). Application of chimeric mice with humanized liver for study of human-specific drug metabolism. Drug Metab Dispos 42:1055–65
  • Bissig KD, Le TT, Woods NB, Verma IM. (2007). Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci USA 104:20507–11
  • Cui L, Yoon S, Schinazi RF, Sommadossi JP. (1995). Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells. J Clin Invest 95:555–63
  • Dalvie D, Obach RS, Kang P, et al. (2009). Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol 22:357–68
  • Dandri M, Burda MR, Török E, et al. (2001). Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 33:981–8
  • De Serres M, Bowers G, Boyle G, et al. (2011). Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism. Xenobiotica 41:464–75
  • Degen PH, Dieterle W, Schneider W, et al. (1988). Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients. Xenobiotica 18:1449–55
  • Faigle JW, Böttcher I, Godbillon J, et al. (1988). A new metabolite of diclofenac sodium in human plasma. Xenobiotica 18:1191–7
  • Fattinger K, Funk C, Pantze M, 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
  • Food and Drug Administration. (2010). Guidance for industry: M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Rockville, MD: FDA
  • Foster JR, Jacobsen M, Kenna G, et al. (2012). Differential effect of troglitazone on the human bile acid transporters, MRP2 and BSEP, in the PXB hepatic chimeric mouse. Toxicol Pathol 40:1106–16
  • Foster JR, Lund G, Sapelnikova S, et al. (2014). Chimeric rodents with humanized liver: bridging the preclinical/clinical trial gap in ADME/toxicity studies. Xenobiotica 44:109–22
  • Garattini E, Terao M. (2012). The role of aldehyde oxidase in drug metabolism. Expert Opin Drug Metab Toxicol 8:487–503
  • Grompe M, Strom S. (2013). Mice with human livers. Gastroenterology 145:1209–14
  • Hasegawa M, Kawai K, Mitsui T, et al. (2011). The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. Biochem Biophys Res Commun 405:405–10
  • Hasegawa M, Tahara H, Inoue R, et al. (2012). Investigation of drug-drug interactions caused by human pregnane X receptor-mediated induction of CYP3A4 and CYP2C subfamilies in chimeric mice with a humanized liver. Drug Metab Dispos 40:474–80
  • He Z, Zhang H, Zhang X, et al. (2010). Liver xeno-repopulation with human hepatocytes in Fah−/−Rag2−/− mice after pharmacological immunosuppression. Am J Pathol 177:1311–19
  • Humbert M, Segal ES, Kiely DG, et al. (2007). Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 30:338–44
  • Igawa Y, Fujitani T, Shah B, et al. (2014). In vitro and in vivo metabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver. Xenobiotica 44:154–63
  • Ikeda T. (2011). Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. Drug Metab Pharmacokinet 26:60–70
  • Inoue T, Nitta K, Sugihara K, et al. (2008). CYP2C9-catalyzed metabolism of S-warfarin to 7-hydroxywarfarin in vivo and in vitro in chimeric mice with humanized liver. Drug Metab Dispos 36:2429–33
  • Jiang L, Li JG, Lan L, et al. (2010). Human hepatoma HepaRG cell line engraftment in severe combined immunodeficient × beige mice using mouse-specific anti-Fas antibody. Transplant Proc 42:3773–8
  • Jones RD, Jones HM, Rowland M, et al. (2011). PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution. J Pharm Sci 100:4074–89
  • Kakuni M, Morita M, Matsuo K, et al. (2012). Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury. Toxicol Lett 214:9–18
  • Kamimura H, Ito S, Nozawa K, et al. (2015). Formation of the accumulative human metabolite and human-specific glutathione conjugate of diclofenac in TK-NOG chimeric mice with humanized livers. Drug Metab Dispos 43:309–16
  • Kamimura H, Nakada N, Suzuki K, et al. (2010). Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites. Drug Metab Pharmacokinet 25:223–35
  • Kato K, Ohbuchi M, Hamamura S, et al. (2015). Development of murine Cyp3a knockout chimeric mice with humanized liver. Drug Metab Dispos 43:1208–17
  • Katoh M, Sawada T, Soeno Y, 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
  • Kitamura S, Sugihara K. (2014). Current status of prediction of drug disposition and toxicity in humans using chimeric mice with humanized liver. Xenobiotica 44:123–34
  • Lee EW, Lai Y, Zhang H, Unadkat JD. (2006). Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine. J Biol Chem 281:16700–06
  • Lipscomb JC, Haddad S, Poet T, Krishnan K. (2012). Physiologically-based pharmacokinetic (PBPK) models in toxicity testing and risk assessment. Adv Exp Med Biol 745:76–95
  • Liu L, Halladay JS, Shin Y, et al. (2011). Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor. Drug Metab Dispos 39:1840–49
  • Mano Y, Usui T, Kamimura H. (2007). Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. . Biopharm Drug Dispos 28:13–18
  • McKenzie R, Fried MW, Sallie R, 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
  • Mercer DF, Schiller DE, Elliott JF, et al. (2001). Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7:927–33
  • Miyaguchi T, Suemizu H, Shimizu M, et al. (2015). Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling. Regul Toxicol Pharmacol 72:71–6
  • Nakada N, Kawamura A, Kamimura H, et al. (2015). Murine Cyp3a knockout chimeric mice with humanized liver: prediction of the metabolic profile of nefazodone in humans. Biopharm Drug Dispos doi: 10.1002/bdd.1990. [Epub ahead of print]
  • Nakada N, Oda K. (2015). Identification and characterization of metabolites of ASP015K, a novel oral Janus kinase inhibitor, in rats, chimeric mice with humanized liver, and humans. Xenobiotica 45:757–65
  • Nishimura T, Hu Y, Wu M, et al. (2013). Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Ther 344:388–96
  • Okumura H, Katoh M, Sawada T, et al. (2007). Humanization of excretory pathway in chimeric mice with humanized liver. Toxicol Sci 97:533–38
  • Peltz G. (2013). Can 'humanized' mice improve drug development in the 21st century? Trends Pharmacol Sci 34:255–60
  • Poulin P, Jones HM, Jones RD, et al. (2011a). PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets. J Pharm Sci 100:4050–73
  • Poulin P, Jones RD, Jones HM, et al. (2011b). PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach. J Pharm Sci 100:4127–57
  • Ring BJ, Chien JY, Adkison KK, et al. (2011). PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessment of prediction methods of human clearance. J Pharm Sci 100:4090–110
  • Samuelsson K, Pickup K, Sarda S, et al. (2014). Troglitazone metabolism and transporter effects in chimeric mice: a comparison between chimeric humanized and chimeric murinized FRG mice. Xenobiotica 44:186–95
  • Sanoh S, Horiguchi A, Sugihara K, et al. (2012a). 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
  • Sanoh S, Naritomi Y, Fujimoto M, et al. (2015). Predictability of plasma concentration-time curves in humans using single-species allometric scaling of chimeric mice with humanized liver. Xenobiotica 45:605–14
  • Sanoh S, Nozaki K, Murai H, et al. (2012b). Prediction of human metabolism of FK3453 by aldehyde oxidase using chimeric mice transplanted with human or rat hepatocytes. Drug Metab Dispos 40:76–82
  • Sanoh S, Ohta S. (2014). Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics. Biopharm Drug Dispos 35:71–86
  • Sato Y, Yamada H, Iwasaki K, et al. (2008). Human hepatocytes can repopulate mouse liver: histopathology of the liver in human hepatocyte-transplanted chimeric mice and toxicologic responses to acetaminophen. Toxicol Pathol 36:581–91
  • Sayama H, Komura H, Kogayu M. (2013). Application of hybrid approach based on empirical and physiological concept for predicting pharmacokinetics in humans-usefulness of exponent on prospective evaluation of predictability. Drug Metab Dispos 41:498–507
  • Schulz-Utermoehl T, Sarda S, Foster JR, et al. (2012). Evaluation of the pharmacokinetics, biotransformation and hepatic transporter effects of troglitazone in mice with humanized livers. Xenobiotica 42:503–17
  • Sharma R, Litchfield J, Atkinson K, et al. (2014). Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator. Drug Metab Dispos 42:1926–39
  • Sharma R, Litchfield J, Bergman A, et al. (2015). Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment. Drug Metab Dispos 43:190–98
  • Suemizu H, Hasegawa M, Kawai K, et al. (2008). Establishment of a humanized model of liver using NOD/Shi-scid IL2Rgnull mice. Biochem Biophys Res Commun 377:248–52
  • Suemizu H, Sota S, Kuronuma M, et al. (2014). Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes. Regul Toxicol Pharmacol 70:468–73
  • Tateno C, Yoshizane Y, Saito N, et al. (2004). Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol 165:901–12
  • Turrini P, Sasso R, Germoni S, et al. (2006). Development of humanized mice for the study of hepatitis C virus infection. Transplant Proc 38:1181–4
  • Vuppugalla R, Marathe P, He H, et al. (2011). PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach. J Pharm Sci 100:4111–26
  • Wajima T, Yano Y, Fukumura K, Oguma T. (2004). Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles. J Pharm Sci 93:1890–900
  • Xu D, Nishimura T, Nishimura S, 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
  • Xu D, Wu M, Nishimura S, et al. (2015). Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity. J Pharmacol Exp Ther 352:274–80
  • Yamada T, Okuda Y, Kushida M, et al. (2014). Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver. Toxicol Sci 142:137–57
  • Yamashita M, Suemizu H, Murayama N, et al. (2014). Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling. Regul Toxicol Pharmacol 70:214–21
  • Yamazaki H, Kuribayashi S, Inoue T, et al. (2015). Zone analysis by two-dimensional electrophoresis with accelerator mass spectrometry of in vivo protein bindings of idiosyncratic hepatotoxicants troglitazone and flutamide bioactivated in chimeric mice with humanized liver. Toxicol Res 4:106–11
  • Zhang T, Heimbach T, Lin W, et al. (2015). Prospective predictions of human pharmacokinetics for eighteen compounds. J Pharm Sci 104:2795–806

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.