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First published on March 10, 2008; DOI: 10.1124/dmd.107.019075

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Received for publication October 1, 2007.
Revised March 2, 2008.
Accepted for publication March 5, 2008.

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide In vivo and In vitro in Chimeric Mice with Humanized Liver

Shigeyuki Kitamura 1*, Kayoko Nitta 1, Yoshitaka Tayama 1, Chiaki Tanoue 1, Kazumi Sugihara 1, Tae Inoue 2, Tohru Horie 2, Shigeru Ohta 1

1 Hiroshima University 2 PheonixBio Co., Ltd.

* Address correspondence to: E-mail: skitamu{at}hiroshima-u.ac.jp

Abstract

Aldehyde oxidase-mediated oxidation of N1-methylnicotinamide to N1-methyl-2-pyridine-5-carboxamide (2-PY) and N1-methyl-4-pyridone-5-carboxamide (4-PY) in chimeric mice constructed by transplanting human hepatocytes into uPA+/+/SCID mice was examined in vivo and in vitro. The activity in liver cytosol of chimeric mice with a high replacement index was about four-fold higher than that in control mice. Further, the oxidation products in control mice were 2-PY and 4-PY, while in chimeric mice, the major product was 2-PY, as in humans. The aldehyde oxidase in chimeric mouse liver was confirmed to be of human type by immunoblotting analysis. The ratio of pyridones (2-PY/4-PY) excreted in the urine of chimeric mice was closer to that of humans than to that of control mice. Thus, the aldehyde oxidase in chimeric mice has human-type functional characteristics.


Key words: hepatocytes, human pharmacokinetics, in vitro-in vivo prediction, in vitro-in vivo scaling


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T. Inoue, K. Nitta, K. Sugihara, T. Horie, S. Kitamura, and S. Ohta
CYP2C9-Catalyzed Metabolism of S-Warfarin to 7-Hydroxywarfarin in Vivo and in Vitro in Chimeric Mice with Humanized Liver
Drug Metab. Dispos., December 1, 2008; 36(12): 2429 - 2433.
[Abstract] [Full Text] [PDF]


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