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Approach for in Vivo Protein Binding of 5-n-Butyl-pyrazolo[1,5-a]pyrimidine Bioactivated in Chimeric Mice with Humanized Liver by Two-Dimensional Electrophoresis with Accelerator Mass Spectrometry

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Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan, Preclinical Assessment Department, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima 772-8601, Japan, PhoenixBio, Co., Higashi-Hiroshima, Hiroshima 739-0046, Japan, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan, and Towa Environment Science Co., Suminoe-ku, Osaka 559-0034, Japan
* Corresponding author. Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. Tel/Fax: +81-42-721-1406. E-mail: [email protected]
†Showa Pharmaceutical University.
‡Otsuka Pharmaceutical Factory, Inc.
§PhoenixBio Co.
∥Hiroshima University.
⊥Towa Environment Science Co.
Cite this: Chem. Res. Toxicol. 2010, 23, 1, 152–158
Publication Date (Web):November 24, 2009
https://doi.org/10.1021/tx900323a
Copyright © 2009 American Chemical Society

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    Abstract

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    Drug development of a potential analgesic agent 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine was withdrawn because of its limited hepatotoxic effects in humans that could not be predicted from regulatory animal or in vitro studies. In vivo formation of glutathione conjugates and covalent binding of a model compound 5-n-butyl-pyrazolo[1,5-a]pyrimidine were investigated in the present study after intravenous administration to chimeric mice with a human or rat liver because of an interesting capability of human cytochrome P450 1A2 in forming a covalently bound metabolite in vitro. Rapid distribution and elimination of radiolabeled 5-n-butyl-pyrazolo[1,5-a]pyrimidine in plasma or liver fractions were seen in chimeric mice after intravenous administration. However, similar covalent binding in liver was detected over 0.17−24 h after intravenous administration. Radio-LC analyses revealed that the chimeric mice with humanized liver preferentially gave the 3-hydroxylated metabolite and its glutathione conjugate in the plasma and liver. On the contrary, chimeric mice with a rat liver had some rat-specific metabolites in vivo. Analyses by electrophoresis with accelerator mass spectrometry of in vivo radiolabeled liver proteins in chimeric mice revealed that bioactivated 5-n-butyl-pyrazolo[1,5-a]pyrimidine bound nonspecifically to a variety of microsomal proteins including human P450 1A2 as well as cytosolic proteins in the livers from chimeric mice with humanized liver. These results suggest that the hepatotoxic model compound 5-n-butyl-pyrazolo[1,5-a]pyrimidine was activated by human liver microsomal P450 1A2 to reactive intermediate(s) in vivo in humanized chimeric mice and could relatively nonspecifically bind to biomolecules such as P450 1A2 and other proteins.

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