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Research ArticleArticle

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

J. Andrew Williams, Barbara J. Ring, Varon E. Cantrell, David R. Jones, James Eckstein, Kenneth Ruterbories, Mitchell A. Hamman, Stephen D. Hall and Steven A. Wrighton
Drug Metabolism and Disposition August 2002, 30 (8) 883-891; DOI: https://doi.org/10.1124/dmd.30.8.883
J. Andrew Williams
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Barbara J. Ring
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Varon E. Cantrell
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David R. Jones
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James Eckstein
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Kenneth Ruterbories
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Mitchell A. Hamman
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Stephen D. Hall
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Steven A. Wrighton
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Abstract

The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, but recent evidence indicates that CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A forms for 10 substrates, incubations were performed using a consistent molar ratio (1:7:9) of recombinant CYP3A, P450 reductase, and cytochrome b5. A wide range of substrate concentrations was examined to determine the best fit to kinetic models for metabolite formation. In general, Km orS50 values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct comparison of these P450 forms, clearance to the metabolites was determined as a linear relationship of rate of metabolite formation for the lowest substrate concentrations examined. The clearance for 1′-hydroxy midazolam formation at low substrate concentrations was similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance values at low substrate concentrations were 2 to 20 times lower for the other biotransformations. The clearance values for CYP3A7-catalyzed metabolite formation at low substrate concentrations were substantially lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH triazolam, and N-desmethyl diltiazem (CYP3A5 ≈ CYP3A7). The CYP3A forms demonstrated regioselective differences in some of the biotransformations. These results demonstrate an equal or reduced metabolic capability for CYP3A5 compared with CYP3A4 and a significantly lower capability for CYP3A7.

Footnotes

  • ↵1 Current address: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Bldg. 25-235B, 2800 Plymouth Rd., Ann Arbor, Michigan 48105.

  • Abbreviations used are::
    P450
    cytochrome P450
    MDZ
    midazolam
    APZ
    alprazolam
    TZ
    triazolam
    CLAR
    clarithromycin
    TAM
    tamoxifen
    DTZ
    diltiazem
    NIF
    nifedipine
    BFC
    7-benzyloxy-4-trifluoromethylcoumarin
    HFC
    7-hydroxy-4-trifluoromethylcoumarin
    TEST
    testosterone
    E2
    estradiol
    HPLC
    high-performance liquid chromatography
    MIC
    metabolite intermediate complex
    • Received February 5, 2002.
    • Accepted April 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (8)
Drug Metabolism and Disposition
Vol. 30, Issue 8
1 Aug 2002
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Research ArticleArticle

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

J. Andrew Williams, Barbara J. Ring, Varon E. Cantrell, David R. Jones, James Eckstein, Kenneth Ruterbories, Mitchell A. Hamman, Stephen D. Hall and Steven A. Wrighton
Drug Metabolism and Disposition August 1, 2002, 30 (8) 883-891; DOI: https://doi.org/10.1124/dmd.30.8.883

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Research ArticleArticle

Comparative Metabolic Capabilities of CYP3A4, CYP3A5, and CYP3A7

J. Andrew Williams, Barbara J. Ring, Varon E. Cantrell, David R. Jones, James Eckstein, Kenneth Ruterbories, Mitchell A. Hamman, Stephen D. Hall and Steven A. Wrighton
Drug Metabolism and Disposition August 1, 2002, 30 (8) 883-891; DOI: https://doi.org/10.1124/dmd.30.8.883
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