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Research ArticleArticle

The Proton Pump Inhibitor, Omeprazole, but Not Lansoprazole or Pantoprazole, Is a Metabolism-Dependent Inhibitor of CYP2C19: Implications for Coadministration with Clopidogrel

Brian W. Ogilvie, Phyllis Yerino, Faraz Kazmi, David B. Buckley, Amin Rostami-Hodjegan, Brandy L. Paris, Paul Toren and Andrew Parkinson
Drug Metabolism and Disposition November 2011, 39 (11) 2020-2033; DOI: https://doi.org/10.1124/dmd.111.041293
Brian W. Ogilvie
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Phyllis Yerino
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Faraz Kazmi
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David B. Buckley
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Amin Rostami-Hodjegan
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Brandy L. Paris
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Paul Toren
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Abstract

As a direct-acting inhibitor of CYP2C19 in vitro, lansoprazole is more potent than omeprazole and other proton pump inhibitors (PPIs), but lansoprazole does not cause clinically significant inhibition of CYP2C19 whereas omeprazole does. To investigate this apparent paradox, we evaluated omeprazole, esomeprazole, R-omeprazole, lansoprazole, and pantoprazole for their ability to function as direct-acting and metabolism-dependent inhibitors (MDIs) of CYP2C19 in pooled human liver microsomes (HLM) as well as in cryopreserved hepatocytes and recombinant CYP2C19. In HLM, all PPIs were found to be direct-acting inhibitors of CYP2C19 with IC50 values varying from 1.2 μM [lansoprazole; maximum plasma concentration (Cmax) = 2.2 μM] to 93 μM (pantoprazole; Cmax = 6.5 μM). In addition, we identified omeprazole, esomeprazole, R-omeprazole, and omeprazole sulfone as MDIs of CYP2C19 (they caused IC50 shifts after a 30-min preincubation with NADPH-fortified HLM of 4.2-, 10-, 2.5-, and 3.2-fold, respectively), whereas lansoprazole and pantoprazole were not MDIs (IC50 shifts < 1.5-fold). The metabolism-dependent inhibition of CYP2C19 by omeprazole and esomeprazole was not reversed by ultracentrifugation, suggesting that the inhibition was irreversible (or quasi-irreversible), whereas ultracentrifugation largely reversed such effects of R-omeprazole. Under various conditions, omeprazole inactivated CYP2C19 with KI (inhibitor concentration that supports half the maximal rate of inactivation) values of 1.7 to 9.1 μM and kinact (maximal rate of enzyme inactivation) values of 0.041 to 0.046 min−1. This study identified omeprazole, and esomeprazole, but not R-omeprazole, lansoprazole, or pantoprazole, as irreversible (or quasi-irreversible) MDIs of CYP2C19. These results have important implications for the mechanism of the clinical interaction reported between omeprazole and clopidogrel, as well as other CYP2C19 substrates.

Footnotes

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

    doi:10.1124/dmd.111.041293.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    PPI
    proton pump inhibitor
    AUC
    area under the plasma concentration versus time curve
    CLint
    in vitro intrinsic clearance
    Cmax
    maximum plasma concentration
    P450
    cytochrome P450
    DDI
    drug-drug interaction
    EM
    extensive metabolizer
    HLM
    human liver microsomes
    Ki
    inhibition constant
    KI
    inhibitor concentration that supports half the maximal rate of inactivation
    kinact
    maximal rate of enzyme inactivation
    LC/MS-MS
    liquid chromatography/tandem mass spectrometry
    MTDI
    University of Washington Metabolism and Transport Drug Interaction database
    MDI
    metabolism-dependent inhibitor
    FDA
    U.S. Food and Drug Administration
    DMSO
    dimethyl sulfoxide
    PM
    poor metabolizer
    MSM
    mechanistic state model
    MDM
    mechanistic dynamic model
    amu
    atomic mass units.

  • Received June 22, 2011.
  • Accepted July 27, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (11)
Drug Metabolism and Disposition
Vol. 39, Issue 11
1 Nov 2011
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Research ArticleArticle

OMEPRAZOLE IS A METABOLISM-DEPENDENT INHIBITOR OF CYP2C19

Brian W. Ogilvie, Phyllis Yerino, Faraz Kazmi, David B. Buckley, Amin Rostami-Hodjegan, Brandy L. Paris, Paul Toren and Andrew Parkinson
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2020-2033; DOI: https://doi.org/10.1124/dmd.111.041293

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Research ArticleArticle

OMEPRAZOLE IS A METABOLISM-DEPENDENT INHIBITOR OF CYP2C19

Brian W. Ogilvie, Phyllis Yerino, Faraz Kazmi, David B. Buckley, Amin Rostami-Hodjegan, Brandy L. Paris, Paul Toren and Andrew Parkinson
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2020-2033; DOI: https://doi.org/10.1124/dmd.111.041293
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