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Research ArticleArticle

Testosterone, 7-Benzyloxyquinoline, and 7-Benzyloxy-4-trifluoromethyl-coumarin Bind to Different Domains within the Active Site of Cytochrome P450 3A4

Ping Lu, Yuh Lin, A. David Rodrigues, Thomas H. Rushmore, Thomas A. Baillie and Magang Shou
Drug Metabolism and Disposition November 2001, 29 (11) 1473-1479;
Ping Lu
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Yuh Lin
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A. David Rodrigues
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Thomas H. Rushmore
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Thomas A. Baillie
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Magang Shou
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Abstract

Testosterone, 7-benzyloxyquinoline, and 7-benzyloxy-4-trifluoromethyl-coumarin, marker substrates for cytochrome P450 3A4 are commonly used within the pharmaceutical industry to screen new chemical entities as inhibitors of CYP3A4 in a high-throughput manner to predict the potential for drug-drug interactions. However, it has been observed that inhibition data obtained with a given CYP3A4 probe substrate may not correlate well with results from a different probe. As a consequence, the choice of the probe compound becomes an important consideration in such screens. In the present study, kinetic interactions between either two of the above three substrates were evaluated, and three-dimensional nonlinear regression analysis was performed to understand the kinetic mechanisms of drug interaction. Our results demonstrate that the kinetic interaction between each pair of substrates does not appear to be competitive and that the interactions are characterized by an unchanged or a decrease in both apparent Km (a = 0.21−0.72, a change of Km in the absence of the effector) and Vmax (α andβ = 0.09−0.75, changes ofVmax in the absence of the effector). These data suggest that 1) the three substrates bind to different domains; 2) at least two substrates can coexist in the active site of CYP3A4; and 3) the two bound substrates interact kinetically with each other (e.g., through steric hindrance), thereby leading to a change in both apparent kinetic parameters and partial inhibition. Selection of multiple substrates, which are shown not to be competitive, is necessary to accurately predict CYP3A4 inhibition and the potential for drug-drug interaction.

Footnotes

  • Abbreviations used are::
    P450
    cytochrome P450
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    BQ
    7-benzyloxyquinoline
    BFC
    7-benzyloxy-4-trifluoromethyl-coumarin
    OR
    cytochrome P450 oxidoreductase
    HPLC
    high-pressure liquid chromatography
    NCE
    new chemical entities
    RSS
    residual sum of squares
    • Received June 19, 2001.
    • Accepted August 6, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Testosterone, 7-Benzyloxyquinoline, and 7-Benzyloxy-4-trifluoromethyl-coumarin Bind to Different Domains within the Active Site of Cytochrome P450 3A4

Ping Lu, Yuh Lin, A. David Rodrigues, Thomas H. Rushmore, Thomas A. Baillie and Magang Shou
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1473-1479;

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Research ArticleArticle

Testosterone, 7-Benzyloxyquinoline, and 7-Benzyloxy-4-trifluoromethyl-coumarin Bind to Different Domains within the Active Site of Cytochrome P450 3A4

Ping Lu, Yuh Lin, A. David Rodrigues, Thomas H. Rushmore, Thomas A. Baillie and Magang Shou
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1473-1479;
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