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Research ArticleArticle

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

J. Matthew Hutzler, Young-Sun Yang, Daniel Albaugh, Cody L. Fullenwider, Jennifer Schmenk and Michael B. Fisher
Drug Metabolism and Disposition February 2012, 40 (2) 267-275; DOI: https://doi.org/10.1124/dmd.111.042861
J. Matthew Hutzler
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Young-Sun Yang
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Daniel Albaugh
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Cody L. Fullenwider
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Jennifer Schmenk
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Michael B. Fisher
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Abstract

Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. Estimated hepatic clearance (Clh) for BIBX1382, carbazeran, O6-benzylguanine, zaleplon, and XK-469 using cryopreserved hepatocytes was 18, 17, 12, <4.3, and <4.3 ml · min−1 · kg−1, respectively. The observed metabolic clearance in cryopreserved hepatocytes was confirmed to be a result of AO-mediated metabolism via two approaches. Metabolite identification after incubations in the presence of H218O confirmed that the predominant oxidative metabolite was generated by AO, as expected isotope patterns in mass spectra were observed after analysis by high-resolution mass spectrometry. Second, clearance values were efficiently attenuated upon coincubation with hydralazine, an inhibitor of AO. The low exposure after oral doses of BIBX1382 and carbazeran (∼5% F) would have been fairly well predicted using simple hepatic extraction (fh) values derived from cryopreserved hepatocytes. In addition, the estimated hepatic clearance value for O6-benzylguanine was within ∼80% of the observed total clearance in humans after intravenous administration (15 ml · min−1 · kg−1), indicating a reasonable level of quantitative activity from this in vitro system. However, a 3.5-fold underprediction of total clearance was observed for zaleplon, despite the 5-oxo metabolite being clearly observed. These data taken together suggest that the use of cryopreserved hepatocytes may be a practical approach for assessing AO-mediated metabolism in discovery and potentially useful for predicting hepatic clearance of AO substrates.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:http://dx.doi.org/10.1124/dmd.111.042861.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AO
    aldehyde oxidase
    Clint
    intrinsic clearance
    Clh
    hepatic clearance
    Qh
    liver blood flow
    XIC
    extracted ion chromatogram
    WME
    Williams' Medium E
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry.

  • Received September 21, 2011.
  • Accepted October 26, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 2012
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Research ArticleArticle

ALDEHYDE OXIDASE ACTIVITY IN CRYOPRESERVED HEPATOCYTES

J. Matthew Hutzler, Young-Sun Yang, Daniel Albaugh, Cody L. Fullenwider, Jennifer Schmenk and Michael B. Fisher
Drug Metabolism and Disposition February 1, 2012, 40 (2) 267-275; DOI: https://doi.org/10.1124/dmd.111.042861

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Research ArticleArticle

ALDEHYDE OXIDASE ACTIVITY IN CRYOPRESERVED HEPATOCYTES

J. Matthew Hutzler, Young-Sun Yang, Daniel Albaugh, Cody L. Fullenwider, Jennifer Schmenk and Michael B. Fisher
Drug Metabolism and Disposition February 1, 2012, 40 (2) 267-275; DOI: https://doi.org/10.1124/dmd.111.042861
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