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Research ArticleArticle

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition December 2011, 39 (12) 2381-2386; DOI: https://doi.org/10.1124/dmd.111.041806
John T. Barr
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Abstract

During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following: Km = 8.0 ± 0.4 μM and Vmax = 4.3 ± 0.1 nmol · min−1 · mg protein−1. Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 μM. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one through a strictly competitive mode. A ratio of the Kii and Kis values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (Kii/Kis values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the Ki value relative to the inhibitor concentration in human plasma, having a calculated [I]/Ki value of 0.4 and 0.8, respectively.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM84546].

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

    doi:10.1124/dmd.111.041806.

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

  • ABBREVIATIONS:

    DDI
    drug-drug interaction
    AOX
    aldehyde oxidase
    HLC
    human liver cytosol
    DMSO
    dimethyl sulfoxide
    MS
    mass spectrometry
    LB
    Lineweaver-Burk
    DCPIP
    2,6-dichlorophenolindophenol
    E-S
    enzyme-substrate.

  • Received July 20, 2011.
  • Accepted September 19, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Research ArticleArticle

INHIBITION OF HUMAN LIVER AOX IN DRUG-DRUG INTERACTIONS

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2381-2386; DOI: https://doi.org/10.1124/dmd.111.041806

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Research ArticleArticle

INHIBITION OF HUMAN LIVER AOX IN DRUG-DRUG INTERACTIONS

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2381-2386; DOI: https://doi.org/10.1124/dmd.111.041806
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