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

Chemical Research in Toxicology
Hiroshi YamazakiShigeru Ohta

Abstract

Drug development of a potential analgesic agent 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine was withdrawn because of its limited hepatotoxic effects in humans that could not be predicted from regulatory animal or in vitro studies.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 liv...Continue Reading

References

Nov 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Laura P JamesJack A Hinson
Aug 28, 2004·The American Journal of Pathology·Chise TatenoKatsutoshi Yoshizato
Oct 13, 2005·Human Gene Therapy·Kentaro EmotoKatsutoshi Yoshizato
Jan 13, 2006·Annual Review of Pharmacology and Toxicology·Frank J Gonzalez, Ai-Ming Yu
Dec 7, 2007·Chemical Research in Toxicology·F Peter Guengerich
Feb 6, 2008·Toxicology·Miki KatohTsuyoshi Yokoi
May 12, 2009·Drug Metabolism and Pharmacokinetics·Tae InoueShigeru Ohta

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Citations

Mar 5, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Mark De SerresCosette Serabjit-Singh
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Naoyuki Nakada, Kazuo Oda
May 31, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Kristin SamuelssonIan D Wilson
Dec 18, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shigeyuki Kitamura, Kazumi Sugihara
Jan 15, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Kristin SamuelssonIan Wilson
Jul 9, 2010·Drug Metabolism and Pharmacokinetics·Hidetaka KamimuraTakashi Usui
Apr 6, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Keigo NakayamaYukihiro Nomura
Sep 1, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Seigo SanohShigeru Ohta
Oct 11, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Seigo SanohShigeru Ohta
Nov 4, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Seigo SanohShigeru Ohta
May 17, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kota KatoChise Tateno

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