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Research ArticleArticle

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

Landry K. Kamdem, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition January 2011, 39 (1) 98-105; DOI: https://doi.org/10.1124/dmd.110.032276
Landry K. Kamdem
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (L.K.K., D.A.F., Z.D.)
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David A. Flockhart
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (L.K.K., D.A.F., Z.D.)
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Zeruesenay Desta
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (L.K.K., D.A.F., Z.D.)
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Abstract

Exemestane is a potent and irreversible steroidal aromatase inhibitor drug used for the treatment of estrogen receptor-positive breast cancer. Our aim was to identify and assess the contribution of the specific cytochromes P450 (P450s) responsible for exemestane primary in vitro metabolism. With the use of high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques, 17-hydroexemestane (MI) formation and 6-hydroxymethylexemestane (MII) formation were found to be the predominant exemestane metabolic pathways. In a bank of 15 well characterized human liver microsomes with known P450 isoform-specific activities, the MI formation rate correlated significantly with CYP1A2 (Spearman r = 0.60, p = 0.02) and CYP4A11 (Spearman r = 0.67, p = 0.01) isoform-specific activities, whereas the MII production rate significantly correlated with CYP2B6 (Spearman r = 0.57, p = 0.03) and CYP3A (Spearman r = 0.76, p = 0.005) isoform-specific activities. Recombinant CYP1A1 metabolized exemestane to MI with a catalytic efficiency (Clint) of 150 nl/pmol P450 × min that was at least 3.5-fold higher than those of other P450s investigated. Recombinant CYP3A4 catalyzed MII formation from exemestane with a catalytic efficiency of 840 nl/pmol P450 × min that was at least 4-fold higher than those of other P450s investigated. Among a panel of 10 chemical inhibitors tested, only ketoconazole and troleandomycin (CYP3A-specific chemical inhibitors) significantly inhibited the formation of MII by 45 and 95%, respectively. None of them markedly inhibited the formation of MI. In summary, exemestane seems to be metabolized to MI by multiple P450s that include CYP4A11 and CYP1A1/2, whereas its oxidation to MII is primarily mediated by CYP3A.

Footnotes

    • Received January 16, 2010.
    • Accepted September 28, 2010.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant 5U01GM061373-09].

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

    doi:10.1124/dmd.110.032276.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    thioTEPA
    1,1-phosphinothioylidynetrisaziridine
    HPLC
    high-performance liquid chromatography
    HLM
    human liver microsome
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MRM
    multiple reaction monitoring
    amu
    atomic mass units.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

Landry K. Kamdem, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition January 1, 2011, 39 (1) 98-105; DOI: https://doi.org/10.1124/dmd.110.032276

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Research ArticleArticle

In Vitro Cytochrome P450-Mediated Metabolism of Exemestane

Landry K. Kamdem, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition January 1, 2011, 39 (1) 98-105; DOI: https://doi.org/10.1124/dmd.110.032276
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