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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Human Cytochromes P450 Responsible for in Vitro Formation of R- and S-Norfluoxetine

Barbara J. Ring, James A. Eckstein, Jennifer S. Gillespie, Shelly N. Binkley, Mark VandenBranden and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 1044-1050;
Barbara J. Ring
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James A. Eckstein
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Jennifer S. Gillespie
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Shelly N. Binkley
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Mark VandenBranden
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Steven A. Wrighton
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Abstract

The formation of R- andS-norfluoxetine was analyzed in vitro in human liver microsomes. Low apparent Km values forR-norfluoxetine formation of ≤8 μM andS-norfluoxetine of <0.2 μM were determined.R-Norfluoxetine formation rates in a characterized microsomal bank correlated with the catalytic activities for cytochrome P450 (CYP) 2D6, CYP2C9, and CYP2C8. Expressed CYP2C9, CYP2C19, and CYP2D6 formed R-norfluoxetine following incubation with 1 μM R-fluoxetine and exhibited apparentKm values of 9.7, 8.5, and 1.8 μM, respectively. Multivariate correlation analysis identified CYP2C9 and CYP2D6 as significant regressors with R-norfluoxetine formation. Antibodies to the CYP2C subfamily and CYP2D6 each exhibited moderate inhibition of R-norfluoxetine formation. Therefore, CYP2D6 and CYP2C9 contribute to this biotransformation. At pharmacological concentrations of S-fluoxetine,S-norfluoxetine formation rates in the bank of microsomes were found to correlate only with CYP2D6 catalytic activity and only expressed CYP2D6 was found to be capable of formingS-norfluoxetine. Thus, it would appear that both CYP2D6 and CYP2C9 contribute to the formation ofR-norfluoxetine, whereas only CYP2D6 is responsible for the conversion to S-norfluoxetine. Since the enantiomers of fluoxetine and norfluoxetine are inhibitors of CYP2D6, upon chronic dosing, the CYP2D6-mediated metabolism of the fluoxetine enantiomers would likely be inhibited, resulting in R-norfluoxetine formation being mediated by CYP2C9 and S-norfluoxetine formation being mediated by multiple high Kmenzymes.

Footnotes

  • Send reprint requests to: Barbara J. Ring, Lilly Corporate Center, Mail Drop 0730, Eli Lilly and Co., Indianapolis, IN 46285. E-mail:ring_barbara_j{at}lilly.com

  • Abbreviations:
    CYP
    cytochromes P450
    PM
    poor metabolizer of CYP2D6 substrates
    EM
    extensive metabolizer of CYP2D6 substrates
    HL
    human liver
    FMO
    flavin-containing monooxygenase
    HPLC
    high-performance liquid chromatography
    bql
    below quantifiable limit
    • Received September 12, 2000.
    • Accepted February 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Human Cytochromes P450 Responsible for in Vitro Formation of R- and S-Norfluoxetine

Barbara J. Ring, James A. Eckstein, Jennifer S. Gillespie, Shelly N. Binkley, Mark VandenBranden and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1044-1050;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Human Cytochromes P450 Responsible for in Vitro Formation of R- and S-Norfluoxetine

Barbara J. Ring, James A. Eckstein, Jennifer S. Gillespie, Shelly N. Binkley, Mark VandenBranden and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1044-1050;
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