Development and assessment of new risk assessment methods

Title of Research:
12_S01-02-2

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 wasdefined in humans based on metabolic parameters determined experimentally in vitro and/or invivo and physiological parameters derived from the literature. In this study, the PBPK model
basically consists of a chemical absorption compartment, a metabolizing compartment, and acentral compartment for a wide of academic, regulatory, and industrial users. Test chemicals andprimary metabolites, organophosphorus pesticides acephate and chlorpyrifos, herbicidal carbamate
molinate, di(2-ethylhexyl)phthalate, and bisphenol A were evaluated in human bodies by the present
PBPK modeling. 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 November 1, 2013 to February 28, 2015
Topics: The principal Investigator was awarded by Japanese Society for the Study of Xenobiotics.
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Y. Higuchi, K. Kawai, H. Yamazaki, M. Nakamura, F. Bree, C. Guillouzo, and H. Suemizu. The
human hepatic cell line HepaRG cells, possible cell source for steady generation of humanizedliver TK-NOG mice. Xenobiotica 44:146-153, 2014.
N. Murayama, R. van Beuningen, H. Suemizu, Guguen-Guillouzo, C., N. Shibata, K. Yajima, M.
Utoh, M. Shimizu, C. Chesne, M. Nakamura, F. P. Guengerich, R. Houtman, and H. Yamazaki.
Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation ofpregnane X receptor. Chem.Res.Toxicol. 27:304-308, 2014.
M. Yamashita, H. Suemizu, N. Murayama, S. Nishiyama, M. Shimizu, and H. Yamazaki. Humanplasma 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. 70:214-221, 2014.
H. Suemizu, S. Sota, M. Kuronuma, M. Shimizu, and H. Yamazaki. Pharmacokinetics and effects
on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos inchimeric mice transplanted with human hepatocytes. Regul.Toxicol.Pharmacol. 70:468-473, 2014.
K. Adachi, H. Suemizu, N. Murayama, M. Shimizu, and H. Yamazaki. 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. in press (doi:10.1016/j.etap.2015.02.011)
T. Miyaguchi, H. Suemizu, M. Shimizu, S. Shida, S. Nishiyama, R. Takano, N. Murayama, and H.
Yamazaki. 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. in press (doi:10.1016/j.yrtph.2015.03.010).