Development and assessment of new risk assessment methods
Title of Research:
12_S01-02-3

Human physiologically-based pharmacokinetic modelingindustrial chemicals with chimeric mice with humanized liverofPrincipal Investigator: Prof. Hiroshi Yamazaki, PhD (Showa Pharmaceutical University,
Laboratory of Drug Metabolism and Pharmacokinetics), 3-3165, Higashi-tamagawa Gakuen,
Machida,Tokyo
194-8543,
Japan.
(phone)+81-42-721-1406,(e-mail)hyamazak@ac.shoyaku.ac.jp.
Collaborators: Norie Murayama, ibid, (e-mail) muraya_n@ac.shoyaku.ac.jp; Makiko Shimizu,ibid, (e-mail) shimizu@ac.shoyaku.ac.jp; Hiroshi Suemizu, CIEA, (e-mail) suemizu@ciea.or.jp.
Ryoji Takano, Fujitsu Kyushu Systems, (e-mail) takano.r@jp.fujitsu.com
Summary of Research: A simplified physiologically based pharmacokinetic (PBPK) model was
defined in humans using humanized-liver mice, in which the liver has been repopulated withhuman hepatocytes is one of the challenge for evaluation of species differences. In order toovercome limitation of available human hepatocytes, the human hepatic cell line HepaRG wereevaluated as promising donor cells for liver reconstitution in the TK-NOG mouse model. Taken
together, the utility of this simplified PBPK model with humanized mice could be also expanded tothe industry researchers and regulatory authorities to investigate a variety of chemicals.
Timeline: From March 1, 20145 to February 28, 2016
Topics: The principal Investigator was the leading organizer for 19th International Conference onCytochrome P450 (Tokyo, 2015).
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Adachi,K., Suemizu,H., Murayama,N., Shimizu,M., and Yamazaki,H. (2015) Human biofluid
concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimericmice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based
pharmacokinetic modeling. Environ.Toxicol.Pharmacol., 39, 1067-1073.
Miyaguchi,T., Suemizu,H., Shimizu,M., Shida,S., Nishiyama,S., Takano,R., Murayama,N., andYamazaki,H. (2015) Human urine and plasma concentrations of bisphenol A extrapolated frompharmacokinetics established in in vivo experiments with chimeric mice with humanized liver andsemi-physiological pharmacokinetic modeling. Regul.Toxicol.Pharmacol., 72, 71-76.
Nishiyama, S., Suemizu, H., Shibata, N., Guengerich, F. P., and Yamazaki, H. (2015) Simulation ofhuman plasma concentrations of thalidomide and primary 5-hydroxylated metabolites exploredwith pharmacokinetic data in humanized TK-NOG mice. Chem. Res.Toxicol., 28, 2088-2090.
Yamazaki, H., Kunikane, E., Nishiyama, S., Murayama, N., Shimizu, M., Sugiyama, Y., Chiba, K.,
and Ikeda, T. (2015) Human plasma concentrations of tolbutamide and acetaminophen
extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances andsimple physiologically based pharmacokinetic modeling for radio-labeled microdose clinicalstudies. Radioisotopes, 64, 509-519
Murayama,N., Usui,T., Slawny,N., Chesne,C., and Yamazaki,H. (2015) Human HepaRG cells canbe cultured in hanging-drop plates for cytochrome P450 induction and function assays. DrugMetab.Lett., 9, 3-7.
Higuchi, Y., Kawai, K., Kanai, T., Yamazaki, H., Chesne, C., Guguen-Guillouzo, C., and Suemizu,
H. Functional polymer-dependent 3D culture accelerates the differentiation of HepaRG cells intomature hepatocytes. Hepatol.Res., in press
Shida, S. and Yamazaki, H. Human plasma concentrations of five cytochrome P450 probes
extrapolated from pharmacokinetics in dogs and minipigs using physiologically based
pharmacokinetic modeling. Xenobiotica, in press.
Utoh, M., Suemizu, H., Mitsui, M., Kawao, M., Toda, A., Uehara, S., Uno, Y., Shimizu, M., Sasaki,E., and Yamazaki, H. Human plasma concentrations of cytochrome P450 probe cocktails
extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and frompharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling.
Xenobiotica, in press.

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