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Research ArticleArticle

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

Michael B. Fisher, Kwansik Yoon, Marcie L. Vaughn, Timothy J. Strelevitz and Robert S. Foti
Drug Metabolism and Disposition October 2002, 30 (10) 1087-1093; DOI: https://doi.org/10.1124/dmd.30.10.1087
Michael B. Fisher
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Kwansik Yoon
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Marcie L. Vaughn
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Timothy J. Strelevitz
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Robert S. Foti
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Abstract

Liver microsomes, and more recently cryopreserved hepatocytes, are commonly used in the in vitro characterization of the metabolism of new xenobiotics. The flavin-containing monooxygenases (FMO) are a major nonP450 oxidase present in liver microsomes and hepatocytes. Since FMO is known to be thermally labile, and this enzyme may be involved in the metabolic clearance of some drugs, we sought to more completely characterize the metabolic competency of this enzyme in cryopreserved hepatocytes and in liver microsomes preincubated under various conditions using benzydamine as an in vitro and in vivo probe. The metabolism of benzydamine to its major metabolite, theN-oxide, is mediated by FMO3 in humans. We found that the in vitro microsomal t1/2 was 70% longer when incubations were prewarmed at 37°C in the absence of NADPH compared with prewarming in the presence of an NADPH-regenerating system, and N-oxide formation was inhibited >99%. Interestingly, the in vivo clearance predicted from these incubations and from human hepatocytes overpredicted the observed clearance of benzydamine in humans (>10.5 versus 2.4 ml/min/kg). In contrast, rat hepatocytes successfully predicted rat in vivo benzydamine clearance to within ∼30% (>68 versus 48 ml/min/kg). BenzydamineN-oxidation in liver microsomes from all common preclinical species demonstrated heat sensitivity. This information should be considered when extrapolating metabolism data of xenobiotics from these in vitro systems.

Footnotes

  • M.B.F. would like to dedicate this article to Michael R. Rowley (1969–2002).

  • Abbreviations used are::
    ADME
    absorption, distribution, metabolism, and excretion
    P450s
    cytochromes P450
    UGT
    UDP-glucuronosyltransferase
    FMO
    flavin-containing monooxygenase
    HPLC
    high-performance liquid chromatography
    DMSO
    dimethylsulfoxide
    MS/MS
    tandem mass spectrometry
    MRM
    multiple reaction monitoring
    CLint
    microsomal intrinsic clearance
    CLint′
    organ intrinsic clearance
    CLb
    blood clearance
    Q
    blood flow
    fublood
    free fraction in blood
    • Received March 5, 2002.
    • Accepted June 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

Michael B. Fisher, Kwansik Yoon, Marcie L. Vaughn, Timothy J. Strelevitz and Robert S. Foti
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1087-1093; DOI: https://doi.org/10.1124/dmd.30.10.1087

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Research ArticleArticle

Flavin-Containing Monooxygenase Activity in Hepatocytes and Microsomes: In Vitro Characterization and In Vivo Scaling of Benzydamine Clearance

Michael B. Fisher, Kwansik Yoon, Marcie L. Vaughn, Timothy J. Strelevitz and Robert S. Foti
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1087-1093; DOI: https://doi.org/10.1124/dmd.30.10.1087
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