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ToxSci Advance Access published online on March 6, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm041
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver

Hirotoshi Okumura*, Miki Katoh*, Toshiro Sawada*, Miki Nakajima*, Yoshinori Soeno{dagger}, Hikaru Yabuuchi{ddagger}, Toshihiko Ikeda§, Chise Tateno, Katsutoshi Yoshizato,|| and Tsuyoshi Yokoi*,|||

* Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan {dagger} PhoenixBio Co. Ltd., Hiroshima, Japan {ddagger} GenoMembrane Co. Ltd., Yokohama, Japan § Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan Hiroshima Prefectural Institute of Industrial Science and Technology, Cooperative Link of Unique Science and Technology for Economy Revitalization, Hiroshima, Japan || Graduate School of Science, Hiroshima University, Hiroshima, Japan

||| corresponding author: Tsuyoshi Yokoi, Ph.D., Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Tel / Fax : +81-76-234-4407, E-mail: TYOKOI{at}kenroku.kanazawa-u.ac.jp

Received February 3, 2007; revision received February 3, 2007; accepted February 26, 2007


  Abstract

The liver of a chimeric urokinase-type plasminogen activator (uPA)+/+/severe combined immunodificient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0% and 4.7% of the dose, respectively in chimeric mice and were 23.7% and 59.4% of the dose, respectively in control uPA–/–/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA–/–/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.

Key Words: biliary excretion; CMZ; renal excretion; transporters.


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