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Research ArticleMetabolism, Transport, and Pharmacogenomics

In Vitro and In Vivo P-Glycoprotein Transport Characteristics of Rivaroxaban

Mark Jean Gnoth, Ulf Buetehorn, Uwe Muenster, Thomas Schwarz and Steffen Sandmann
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 372-380; DOI: https://doi.org/10.1124/jpet.111.180240
Mark Jean Gnoth
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Ulf Buetehorn
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Uwe Muenster
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Thomas Schwarz
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Steffen Sandmann
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Abstract

Rivaroxaban, an oral, direct factor Xa inhibitor, has a dual mode of elimination in humans, with two-thirds metabolized by the liver and one-third renally excreted unchanged. P-glycoprotein (P-gp) is known to be involved in the absorption, distribution, and excretion of drugs. To investigate whether rivaroxaban is a substrate of P-gp, the bidirectional flux of rivaroxaban across Caco-2, wild-type, and P-gp-overexpressing LLC-PK1 cells was investigated. Furthermore, the inhibitory effect of rivaroxaban toward P-gp was determined. Rivaroxaban exhibited high permeability and polarized transport across Caco-2 cells. Rivaroxaban was shown to be a substrate for, but not an inhibitor of, P-gp. Of a set of potential P-gp inhibitors, ketoconazole and ritonavir, but not clarithromycin or erythromycin, inhibited P-gp-mediated transport of rivaroxaban, with half-maximal inhibitory concentration values in the range of therapeutic plasma concentrations. These findings are in line with observed area under the plasma concentration-time curve increases in clinical drug-drug interaction studies indicating a possible involvement of P-gp in the distribution and excretion of rivaroxaban. In vivo studies in wild-type and P-gp double-knockout mice demonstrated that the impact of P-gp alone on the pharmacokinetics of rivaroxaban is minor. However, in P-gp double-knockout mice, a slight increase in brain concentrations and decreased excretion into the gastrointestinal tract were observed compared with wild-type mice. These studies also demonstrated that brain penetration of rivaroxaban is fairly low. In addition to P-gp, a further transport protein might be involved in the secretion of rivaroxaban.

Footnotes

  • This work was supported by Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research and Development, L.L.C.

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

    doi:10.1124/jpet.111.180240.

  • ABBREVIATIONS:

    VTE
    venous thromboembolism
    AUC
    area under the plasma concentration-time curve
    Cmax
    maximum plasma concentration
    DMSO
    dimethyl sulfoxide
    FDA
    United States Food and Drug Administration
    Ki
    enzyme inhibition constant
    CYP3A4
    cytochrome P450 3A4
    GIT
    gastrointestinal tract
    HBSS
    Hanks' balanced salt solution
    LC
    liquid chromatography
    IC50
    half-maximal inhibitory concentration
    MS/MS
    tandem mass spectrometry
    LSC
    liquid scintillation counting
    Papp
    apparent permeability coefficient
    P-gp
    P-glycoprotein
    TEER
    transepithelial electrical resistance
    BCRP
    breast cancer resistance protein
    A
    apical
    B
    basolateral.

  • Received February 1, 2011.
  • Accepted April 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleMetabolism, Transport, and Pharmacogenomics

In Vitro and In Vivo P-Glycoprotein Transport Characteristics of Rivaroxaban

Mark Jean Gnoth, Ulf Buetehorn, Uwe Muenster, Thomas Schwarz and Steffen Sandmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 372-380; DOI: https://doi.org/10.1124/jpet.111.180240

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Research ArticleMetabolism, Transport, and Pharmacogenomics

In Vitro and In Vivo P-Glycoprotein Transport Characteristics of Rivaroxaban

Mark Jean Gnoth, Ulf Buetehorn, Uwe Muenster, Thomas Schwarz and Steffen Sandmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 372-380; DOI: https://doi.org/10.1124/jpet.111.180240
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