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Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine

David M. Stresser, Andrew K. Mason, Elke S. Perloff, Thuy Ho, Charles L. Crespi, Andre A. Dandeneau, Ling Morgan and Shangara S. Dehal
Drug Metabolism and Disposition April 2009, 37 (4) 695-698; DOI: https://doi.org/10.1124/dmd.108.025726
David M. Stresser
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Andrew K. Mason
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Elke S. Perloff
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Thuy Ho
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Charles L. Crespi
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Andre A. Dandeneau
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Ling Morgan
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Shangara S. Dehal
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Abstract

Fluoxetine [±-N-methyl-3-phenyl-3-[(α, α, (-trifluoro-p-tolyl)oxy]-propylamine)] a selective serotonin reuptake inhibitor, is widely used in treating depression and other serotonin-dependent disease conditions. Racemic, (R)- and (S)-fluoxetine are potent reversible inhibitors of CYP2D6, and the racemate has been shown to be a mechanism-based inhibitor of CYP3A4. Racemic fluoxetine also demonstrates time- and concentration-dependent inhibition of CYP2C19 catalytic activity in vitro. In this study, we compared fluoxetine, its (R)- and (S)-enantiomers, ticlopidine, and S-benzylnirvanol as potential time-dependent inhibitors of human liver microsomal CYP2C19. In a reversible inhibition protocol (30 min preincubation with liver microsomes without NADPH), we found (R)-, (S)- and racemic fluoxetine to be moderate inhibitors with IC50 values of 21, 93, and 27 μM, respectively. However, when the preincubation was supplemented with NADPH, IC50 values shifted to 4.0, 3.4, and 3.0 μM, respectively resulting in IC50 shifts of 5.2-, 28-, and 9.3-fold. Ticlopidine showed a 1.8-fold shift in IC50 value, and S-benzylnirvanol shifted right (0.41-fold shift). Follow-up KI and kinact determinations with fluoxetine confirmed time-dependent inhibition [KI values of 6.5, 47, and 14 μM; kinact values of 0.023, 0.085, 0.030 min–1 for (R)-, (S)-, and racemate, respectively]. Although the (S)-isomer exhibits a much lower affinity for CYP2C19 inactivation relative to the (R)-enantiomer, it exhibits a more rapid rate of inactivation. Racemic norfluoxetine exhibited an 11-fold shift (18–1.5 μM) in IC50 value, suggesting that conversion of fluoxetine to this metabolite represents a metabolic pathway leading to time-dependent inhibition. These data provide an improved understanding of the drug-interaction potential of fluoxetine.

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  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.025726.

  • ABBREVIATIONS: P450, cytochrome P450; HLM, human liver microsomes; MS, mass spectrometry; KI, inhibition constant; kinact, maximal inactivation rate constant.

    • Received November 19, 2008.
    • Accepted January 12, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (4)
Drug Metabolism and Disposition
Vol. 37, Issue 4
1 Apr 2009
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OtherShort Communication

Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine

David M. Stresser, Andrew K. Mason, Elke S. Perloff, Thuy Ho, Charles L. Crespi, Andre A. Dandeneau, Ling Morgan and Shangara S. Dehal
Drug Metabolism and Disposition April 1, 2009, 37 (4) 695-698; DOI: https://doi.org/10.1124/dmd.108.025726

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OtherShort Communication

Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine

David M. Stresser, Andrew K. Mason, Elke S. Perloff, Thuy Ho, Charles L. Crespi, Andre A. Dandeneau, Ling Morgan and Shangara S. Dehal
Drug Metabolism and Disposition April 1, 2009, 37 (4) 695-698; DOI: https://doi.org/10.1124/dmd.108.025726
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