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Research ArticleArticle

CYP2B6 Mediates the In Vitro Hydroxylation of Bupropion: Potential Drug Interactions with Other Antidepressants

Leah M. Hesse, Karthik Venkatakrishnan, Michael H. Court, Lisa L. von Moltke, Su X. Duan, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition October 2000, 28 (10) 1176-1183;
Leah M. Hesse
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Karthik Venkatakrishnan
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Michael H. Court
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Lisa L. von Moltke
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Su X. Duan
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Richard I. Shader
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David J. Greenblatt
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Abstract

The in vitro biotransformation of bupropion to hydroxybupropion was studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (±S.E.) Km in four human liver microsomes was 89 (±14) μM. In microsomes containing cDNA-expressed CYPs, hydroxybupropion formation was mediated only by CYP2B6 at 50 μM bupropion (Km 85 μM). A CYP2B6 inhibitory antibody produced more than 95% inhibition of bupropion hydroxylation in four human livers. Bupropion hydroxylation activity at 250 μM was highly correlated with S-mephenytoinN-demethylation activity (yielding nirvanol), another CYP2B6-mediated reaction, in a panel of 32 human livers (r = 0.94). The CYP2B6 content of 12 human livers highly correlated with bupropion hydroxylation activity (r = 0.96). Thus bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform. IC50values for inhibition of a CYP2D6 index reaction (dextromethorphanO-demethylation) by bupropion and hydroxybupropion were 58 and 74 μM, respectively. This suggests a low inhibitory potency versus CYP2D6, the clinical importance of which is not established. Since bupropion is frequently coadministered with other antidepressants, IC50 values (μM) for inhibition of bupropion hydroxylation were determined as follows: paroxetine (1.6), fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9), fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4). Bupropion hydroxylation was only weakly inhibited by venlafaxine,O-desmethylvenlafaxine, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by a number of newer antidepressants suggests the potential for clinical drug interactions.

Footnotes

  • Send reprint requests to: Dr. David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: DJ.Greenblatt{at}tufts.edu

  • This work was supported in part by Grants MH34223, MH01237, and RR00054 from the Department of Health and Human Services. M. H. Court was supported in part by a Special Emphasis Research Career Award from the National Institutes of Health (K01-RR-00104).

  • Abbreviations used are::
    SSRI
    selective serotonin reuptake inhibitor
    Vmax
    maximum reaction velocity
    Km
    substrate concentration corresponding to 50% Vmax
    CYP
    cytochrome P450
    IC50
    inhibitor concentration at which 50% inhibition is achieved
    Emax
    maximal degree of inhibition
    HRP
    horseradish peroxidase
    • Received May 1, 2000.
    • Accepted June 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (10)
Drug Metabolism and Disposition
Vol. 28, Issue 10
1 Oct 2000
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Research ArticleArticle

CYP2B6 Mediates the In Vitro Hydroxylation of Bupropion: Potential Drug Interactions with Other Antidepressants

Leah M. Hesse, Karthik Venkatakrishnan, Michael H. Court, Lisa L. von Moltke, Su X. Duan, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1176-1183;

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Research ArticleArticle

CYP2B6 Mediates the In Vitro Hydroxylation of Bupropion: Potential Drug Interactions with Other Antidepressants

Leah M. Hesse, Karthik Venkatakrishnan, Michael H. Court, Lisa L. von Moltke, Su X. Duan, Richard I. Shader and David J. Greenblatt
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1176-1183;
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