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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

O-Dealkylation of Fluoxetine in Relation toCYP2C19 Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

Zhao-Qian Liu, Bing Zhu, Yun-Fu Tan, Zhi-Rong Tan, Lian-Sheng Wang, Song-Lin Huang, Yan Shu and Hong-Hao Zhou
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 105-111; DOI: https://doi.org/10.1124/jpet.300.1.105
Zhao-Qian Liu
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Bing Zhu
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Yun-Fu Tan
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Zhi-Rong Tan
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Lian-Sheng Wang
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Song-Lin Huang
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Yan Shu
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Hong-Hao Zhou
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Abstract

This work evaluated the kinetic behavior of fluoxetineO-dealkylation in human liver microsomes from differentCYP2C19 genotypes and identified the isoenzymes of cytochrome P450 involved in this metabolic pathway. The kinetics of the ρ-trifluoromethylphenol (TFMP) formation from fluoxetine was determined in human liver microsomes from three homozygous (wt/wt) and three heterozygous (wt/m1) extensive metabolizers (EMs) and three poor metabolizers (PMs) withm1 mutation (m1/m1) with respect to CYP2C19. The formation rate of TFMP was determined by gas chromatograph with electron-capture detection. The kinetics of TFMP formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equation for liver microsomes from CYP2C19 EMs and PMs, respectively. The mean intrinsic clearance (V max/K m) for the high- and low-affinity component was 25.2 μl/min/nmol and 3.8 μl/min/nmol of cytochrome P450 in the homozygous EMs microsomes and 12.8 μl/min/nmol and 2.9 μl/min/nmol of cytochrome P450 in the heterozygous EMs microsomes, respectively. Omeprazole (a CYP2C19 substrate) at a high concentration and triacetyloleandomycin (a selective inhibitor of CYP3A4) substantially inhibitedO-dealkylation of fluoxetine. Furthermore, fluoxetineO-dealkylation was correlated significantly withS-mephenytoin 4′-hydroxylation at a low substrate concentration and midazolam 1′-hydroxylation at a high substrate concentration in liver microsomes of 11 Chinese individuals, respectively. Moreover, there were obvious differences in theO-dealkylation of fluoxetine in liver microsomes from different CYP2C19 genotypes and in microsomal fractions of different human-expressed lymphoblast P450s. The results demonstrated that polymorphic CYP2C19 and CYP3A4 enzymes were the major cytochrome P450 isoforms responsible for fluoxetineO-dealkylation, whereas CYP2C19 catalyzed the high-affinity O-dealkylation of fluoxetine, and its contribution to this metabolic reaction was gene dose-dependent.

Footnotes

  • ↵1 Current address: Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143. E-mail:yans{at}itsa.ucsf.edu

  • This work was supported by China Medical Board of America Grants 92-568 and 99-697.

  • Abbreviations

    CYP
    cytochrome P450
    TFMP
    ρ-trifluoromethylphenol
    DDC
    diethyldithiocarbamate
    EM
    extensive metabolizer
    PM
    poor metabolizer
    GC-ECD
    gas chromatograph with electron-capture detection
    PFBSC
    pentafluorobenzenesulfonyl chloride
    TAO
    triacetyloleandomycin
    • Received February 6, 2001.
    • Accepted August 21, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

    O-Dealkylation of Fluoxetine in Relation toCYP2C19 Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

    Zhao-Qian Liu, Bing Zhu, Yun-Fu Tan, Zhi-Rong Tan, Lian-Sheng Wang, Song-Lin Huang, Yan Shu and Hong-Hao Zhou
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 105-111; DOI: https://doi.org/10.1124/jpet.300.1.105

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    Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

    O-Dealkylation of Fluoxetine in Relation toCYP2C19 Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

    Zhao-Qian Liu, Bing Zhu, Yun-Fu Tan, Zhi-Rong Tan, Lian-Sheng Wang, Song-Lin Huang, Yan Shu and Hong-Hao Zhou
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 105-111; DOI: https://doi.org/10.1124/jpet.300.1.105
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