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Research ArticleArticle

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Lifei Wang, Donglu Zhang, Nirmala Raghavan, Ming Yao, Li Ma, Charles A. Frost, Brad D. Maxwell, Shiang-yuan Chen, Kan He, Theunis C. Goosen, W. Humphreys Griffith and Scott J. Grossman
Drug Metabolism and Disposition March 2010, 38 (3) 448-458; DOI: https://doi.org/10.1124/dmd.109.029694
Lifei Wang
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Donglu Zhang
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Nirmala Raghavan
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Ming Yao
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Li Ma
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Charles A. Frost
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Brad D. Maxwell
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Shiang-yuan Chen
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Kan He
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Theunis C. Goosen
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W. Humphreys Griffith
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This article has a correction. Please see:

  • Correction to “In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies” - May 01, 2010

Abstract

Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC50 values >20 μM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 μM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (fm CYP <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.

Footnotes

  • This work was supported by Bristol-Myers Squibb and by Pfizer.

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

    doi:10.1124/dmd.109.029694.

  • ABBREVIATIONS:

    apixaban, BMS-562247
    1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
    P450
    cytochrome P450
    HLM
    human liver microsome(s)
    HIM
    human intestinal microsome(s)
    HIS
    human intestinal S9
    HKM
    human kidney microsome(s)
    ABT
    1-aminobenzotriazole
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    QC
    quality control
    DMEM
    Dulbecco's modified Eagle's medium
    DMSO
    dimethyl sulfoxide.

    • Received July 24, 2009.
    • Accepted November 24, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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Research ArticleArticle

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Lifei Wang, Donglu Zhang, Nirmala Raghavan, Ming Yao, Li Ma, Charles A. Frost, Brad D. Maxwell, Shiang-yuan Chen, Kan He, Theunis C. Goosen, W. Humphreys Griffith and Scott J. Grossman
Drug Metabolism and Disposition March 1, 2010, 38 (3) 448-458; DOI: https://doi.org/10.1124/dmd.109.029694

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Research ArticleArticle

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Lifei Wang, Donglu Zhang, Nirmala Raghavan, Ming Yao, Li Ma, Charles A. Frost, Brad D. Maxwell, Shiang-yuan Chen, Kan He, Theunis C. Goosen, W. Humphreys Griffith and Scott J. Grossman
Drug Metabolism and Disposition March 1, 2010, 38 (3) 448-458; DOI: https://doi.org/10.1124/dmd.109.029694
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