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Research ArticleArticle

In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase

Michael Zientek, Ying Jiang, Kuresh Youdim and R. Scott Obach
Drug Metabolism and Disposition August 2010, 38 (8) 1322-1327; DOI: https://doi.org/10.1124/dmd.110.033555
Michael Zientek
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Ying Jiang
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Kuresh Youdim
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R. Scott Obach
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Abstract

The ability to predict in vivo clearance from in vitro intrinsic clearance for compounds metabolized by aldehyde oxidase has not been demonstrated. To date, there is no established scaling method for predicting aldehyde oxidase-mediated clearance using in vitro or animal data. This challenge is exacerbated by the fact that rats and dogs, two of the laboratory animal species commonly used to develop in vitro-in vivo correlations of clearance, differ from humans with regard to expression of aldehyde oxidase. The objective of this investigation was to develop an in vitro-in vivo correlation of intrinsic clearance for aldehyde oxidase, using 11 drugs known to be metabolized by this enzyme. The set consisted of methotrexate, XK-469, (±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine (RS-8359), zaleplon, 6-deoxypenciclovir, zoniporide, O6-benzylguanine, N-[(2′-dimethylamino)ethyl]acridine-4-carboxamide (DACA), carbazeran, PF-4217903, and PF-945863. These compounds were assayed using two in vitro systems (pooled human liver cytosol and liver S-9 fractions) to calculate scaled unbound intrinsic clearance, and they were then compared with calculated in vivo unbound intrinsic clearance. The investigation provided a relative scale that can be used for in vitro-in vivo correlation of aldehyde oxidase clearance and suggests limits as to when a potential new drug candidate that is metabolized by this enzyme will possess acceptable human clearance, or when structural modification is required to reduce aldehyde oxidase catalyzed metabolism.

Footnotes

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

    doi:10.1124/dmd.110.033555.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    CLint
    intrinsic clearance
    DACA
    N-[(2′-dimethylamino)ethyl]acridine-4-carboxamide
    RS-8359
    (±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    CL′int,AO
    clearance due to aldehyde oxidase
    CLpo
    oral clearance
    CLrenal
    renal clearance
    CLh
    hepatic clearance.

  • Received March 26, 2010.
  • Accepted May 5, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Research ArticleArticle

In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase

Michael Zientek, Ying Jiang, Kuresh Youdim and R. Scott Obach
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1322-1327; DOI: https://doi.org/10.1124/dmd.110.033555

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Research ArticleArticle

In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase

Michael Zientek, Ying Jiang, Kuresh Youdim and R. Scott Obach
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1322-1327; DOI: https://doi.org/10.1124/dmd.110.033555
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