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Research ArticleArticle

Triethylenethiophosphoramide Is a Specific Inhibitor of Cytochrome P450 2B6: Implications for Cyclophosphamide Metabolism

James M. Rae, Nadia V. Soukhova, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition May 2002, 30 (5) 525-530; DOI: https://doi.org/10.1124/dmd.30.5.525
James M. Rae
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Nadia V. Soukhova
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David A. Flockhart
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Zeruesenay Desta
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Abstract

Cytochrome P450 2B6 is a genetically polymorphic enzyme that is important in the metabolism of a number of clinically used drugs. This enzyme is not as well studied as other cytochrome P450 (P450) isoforms because of the lack of specific antibodies, probe drugs, and inhibitors. Although recent progress has been made toward specific antibodies and probe drugs, a specific enzyme inhibitor is still lacking. Studies suggest that CYP2B6 plays an important role in the 4-hydroxylation of cyclophosphamide and that this reaction can be inhibited by triethylenethiophosphoramide (thioTEPA). We therefore wished to test the hypothesis that thioTEPA is an inhibitor of CYP2B6. Using human liver microsomes (HLMs) and recombinant P450 enzymes, we demonstrated that thioTEPA is a potent and specific inhibitor of CYP2B6. Enzyme activity was reduced 78.1 ± 0.2% by 50 μM thioTEPA when CYP2B6 activity was measured by following the metabolism of 200 μM S-mephenytoin to nirvanol. thioTEPA did not significantly inhibit (<20% at 100 μM) the other isoforms tested (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). thioTEPA seems to be a potent noncompetitive inhibitor of CYP2B6, withKi values of 4.8 ± 0.3 and 6.2 ± 0.7 μM for HLMs and recombinant CYP2B6, respectively, values that are within the plasma concentration range of thioTEPA at therapeutic doses (1.1–18.6 μM). We conclude that thioTEPA is a potent and specific inhibitor of CYP2B6 and that this is the likely mechanism by which thioTEPA inhibits the activation of cyclophosphamide. Furthermore, thioTEPA may prove to be a valuable new tool for the study of this important drug-metabolizing enzyme.

Footnotes

  • ↵1 Current address: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109.

  • ↵2 Currently address: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.

  • This work was funded in part by National Institute of General Medical Sciences (Bethesda, MD) Grants GM61373 (UO1), GM56898 (RO1), and GM08386 (T32).

  • Abbreviations used are::
    P450
    cytochrome P450
    4-OHCP
    4-hydroxycyclophosphamide
    thioTEPA
    triethylenethiophosphoramide
    HLMs
    human liver microsomes
    HPLC
    high-pressure liquid chromatography
    AUC
    area under the curve
    • Received October 29, 2001.
    • Accepted January 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (5)
Drug Metabolism and Disposition
Vol. 30, Issue 5
1 May 2002
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Research ArticleArticle

Triethylenethiophosphoramide Is a Specific Inhibitor of Cytochrome P450 2B6: Implications for Cyclophosphamide Metabolism

James M. Rae, Nadia V. Soukhova, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition May 1, 2002, 30 (5) 525-530; DOI: https://doi.org/10.1124/dmd.30.5.525

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Research ArticleArticle

Triethylenethiophosphoramide Is a Specific Inhibitor of Cytochrome P450 2B6: Implications for Cyclophosphamide Metabolism

James M. Rae, Nadia V. Soukhova, David A. Flockhart and Zeruesenay Desta
Drug Metabolism and Disposition May 1, 2002, 30 (5) 525-530; DOI: https://doi.org/10.1124/dmd.30.5.525
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