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Research ArticleArticle

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Kirk M. Bertelsen, Karthik Venkatakrishnan, Lisa L. von Moltke, R. Scott Obach and David J. Greenblatt
Drug Metabolism and Disposition March 2003, 31 (3) 289-293; DOI: https://doi.org/10.1124/dmd.31.3.289
Kirk M. Bertelsen
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Karthik Venkatakrishnan
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Lisa L. von Moltke
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R. Scott Obach
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David J. Greenblatt
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Abstract

Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estimated by varying the time of preincubation as well as the concentration of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estimation of both an apparent inactivator concentration required for half-maximal inactivation (KI) and the maximal rate constant of inactivation (kINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approximately 8-fold reduction in the IC50 value (0.34 versus 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent kINACT value of 0.17 min−1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metabolism of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.

Footnotes

  • This work was supported by Grants MH-58435, DA-13209, DK/AI-58496, DA-05258, DA-13834, AG-17880, MH-34223, MH-01237, and RR-00054 from the Department of Health and Human Services.

  • Abbreviations used are::
    P450
    cytochrome P450
    MBI
    mechanism-based inhibition
    MIC
    metabolite intermediate complex
    kINACT
    the maximal rate constant of inactivation
    KI
    the inactivator concentration required for half-maximal inactivation
    HLM
    human liver microsome
    HPLC
    high performance liquid chromatography
    • Received September 3, 2002.
    • Accepted November 27, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (3)
Drug Metabolism and Disposition
Vol. 31, Issue 3
1 Mar 2003
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Research ArticleArticle

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Kirk M. Bertelsen, Karthik Venkatakrishnan, Lisa L. von Moltke, R. Scott Obach and David J. Greenblatt
Drug Metabolism and Disposition March 1, 2003, 31 (3) 289-293; DOI: https://doi.org/10.1124/dmd.31.3.289

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Research ArticleArticle

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Kirk M. Bertelsen, Karthik Venkatakrishnan, Lisa L. von Moltke, R. Scott Obach and David J. Greenblatt
Drug Metabolism and Disposition March 1, 2003, 31 (3) 289-293; DOI: https://doi.org/10.1124/dmd.31.3.289
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