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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore

Ann-Charlotte Egnell, Cecilia Eriksson, Nan Albertson, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics December 2003, 307 (3) 878-887; DOI: https://doi.org/10.1124/jpet.103.054999
Ann-Charlotte Egnell
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Cecilia Eriksson
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Nan Albertson
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Brian Houston
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Scott Boyer
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Abstract

Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 μM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v150%, the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v150% 0.04–150 μM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v150% values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v150%] versus [log predicted v150%] = 0.71; r2 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC50 < 1 μM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site.

Footnotes

  • ABBREVIATIONS: QSAR, quantitative structure activity relationship; P450, cytochrome P450; MFC, 7-methoxy-4-trifluoromethyl-coumarin; HFC, 7-hydroxy-4-trifluoromethyl-coumarin.

  • DOI: 10.1124/jpet.103.054999.

    • Received July 1, 2003.
    • Accepted August 25, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 3
1 Dec 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore

Ann-Charlotte Egnell, Cecilia Eriksson, Nan Albertson, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 878-887; DOI: https://doi.org/10.1124/jpet.103.054999

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Generation and Evaluation of a CYP2C9 Heteroactivation Pharmacophore

Ann-Charlotte Egnell, Cecilia Eriksson, Nan Albertson, Brian Houston and Scott Boyer
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 878-887; DOI: https://doi.org/10.1124/jpet.103.054999
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