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Research ArticleArticle

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

Tatyana Zvyaga, Shu-Ying Chang, Cliff Chen, Zheng Yang, Ragini Vuppugalla, Jeremy Hurley, Denise Thorndike, Andrew Wagner, Anjaneya Chimalakonda and A. David Rodrigues
Drug Metabolism and Disposition September 2012, 40 (9) 1698-1711; DOI: https://doi.org/10.1124/dmd.112.045575
Tatyana Zvyaga
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Shu-Ying Chang
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Cliff Chen
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Zheng Yang
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Ragini Vuppugalla
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Jeremy Hurley
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Denise Thorndike
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Andrew Wagner
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Anjaneya Chimalakonda
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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A. David Rodrigues
Lead Profiling (T.Z., J.H., D.T.), and Bioanalytical Technologies (A.W.), Bristol-Myers Squibb, Wallingford, Connecticut; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey (S.-Y.C., C.C., Z.Y., R.V., A.C., A.D.R.)
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Abstract

Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC50 values were greater than 40 μM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC50 = ∼8 μM) and esomeprazole with CYP2C8 (IC50 = 31 μM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC50 ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC50 (IC50 ratio, ≤2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC50 = 0.73 μM) and esomeprazole (IC50 = 3.7 μM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC50 = ∼7.0 μM). Rabeprazole and pantoprazole (IC50 = ≥25 μM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC50 ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 μM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.045575.

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

  • ABBREVIATIONS:

    PPI
    proton pump inhibitor
    P450
    cytochrome P450
    HLM
    human liver microsomes
    r
    recombinant
    CEC
    3-cyano-7-ethoxy-coumarin
    fu,inc
    free fraction in the incubation
    IC50
    concentration of inhibitor that decreases activity by 50% (not corrected for fu,inc)
    IC50(t)
    concentration of inhibitor that decreases activity by 50% after a preincubation time (t)
    IC50(u)
    IC50 corrected for fu,inc
    Cmax
    maximal concentration in plasma
    Cmax,u
    maximal concentration in plasma corrected for free fraction in plasma
    Cmax,portal
    maximal concentration in portal vein
    Cmax,portal,u
    maximal concentration in portal vein corrected for plasma protein binding
    DMSO
    dimethyl sulfoxide
    RF-MS/MS
    RapidFire-mass spectrometry
    KI
    inhibitor concentration that supports half the maximal rate of inactivation
    kinact
    maximal rate of inactivation
    [I]
    concentration of inhibitor
    Ki,u
    Ki corrected for fu,inc
    KI,u
    KI corrected for fu,inc
    kdeg
    rate of P450 (CYP2C19) holoenzyme degradation in the absence of inhibitor
    fa
    fraction absorbed
    ka
    absorption rate constant
    kobs
    rate constant for inactivation at a given concentration of inhibitor
    IV
    intravenous
    AUC
    area under the curve
    fm,2C19
    fraction cleared via CYP2C19
    PM
    poor metabolizer
    EM
    extensive metabolizer
    AUCPM
    AUC in poor metabolizers
    AUCEM
    AUC in extensive metabolizers
    AUCi
    AUC in the presence of inhibitor
    AUCc
    AUC in the absence of inhibitor
    CI
    confidence interval
    FR
    fractional activity remaining.

  • Received March 7, 2012.
  • Accepted May 30, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (9)
Drug Metabolism and Disposition
Vol. 40, Issue 9
1 Sep 2012
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Research ArticleArticle

PPIs AS INHIBITORS OF HUMAN P450s

Tatyana Zvyaga, Shu-Ying Chang, Cliff Chen, Zheng Yang, Ragini Vuppugalla, Jeremy Hurley, Denise Thorndike, Andrew Wagner, Anjaneya Chimalakonda and A. David Rodrigues
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1698-1711; DOI: https://doi.org/10.1124/dmd.112.045575

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Research ArticleArticle

PPIs AS INHIBITORS OF HUMAN P450s

Tatyana Zvyaga, Shu-Ying Chang, Cliff Chen, Zheng Yang, Ragini Vuppugalla, Jeremy Hurley, Denise Thorndike, Andrew Wagner, Anjaneya Chimalakonda and A. David Rodrigues
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1698-1711; DOI: https://doi.org/10.1124/dmd.112.045575
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