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Research ArticleArticle

Investigation of the Involvement of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 in the Efflux of Ximelagatran and Its Metabolites by Using Short Hairpin RNA Knockdown in Caco-2 Cells

Malin Darnell, Johan E. Karlsson, Albert Owen, Ismael J. Hidalgo, Jibin Li, Wei Zhang and Tommy B. Andersson
Drug Metabolism and Disposition March 2010, 38 (3) 491-497; DOI: https://doi.org/10.1124/dmd.109.029967
Malin Darnell
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Johan E. Karlsson
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Albert Owen
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Ismael J. Hidalgo
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Jibin Li
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Wei Zhang
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Tommy B. Andersson
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Abstract

Liver and bile secretion can be an important first-pass and clearance route for drug compounds and also the site of several drug-drug interactions. In the clinical program for ximelagatran development, an unexpected effect of erythromycin on the pharmacokinetics of the direct thrombin inhibitor ximelagatran and its metabolites was detected. This interaction was believed to be mediated by inhibition of drug transporters, which normally extrude the drug into the bile. Previous Caco-2 cell experiments indicated the involvement of an active efflux mechanism for ximelagatran, hydroxy-melagatran, and melagatran possibly mediated by P-glycoprotein (P-gp). However, the inhibitors used may not have been specific enough and the possibility that transporters other than P-gp were important in the Caco-2 cell assay cannot be excluded. In this study we used RNA interference, a post-transcriptional gene silencing mechanism in which mRNA is degraded in a sequence-specific manner, to specifically knock down P-gp or multidrug resistance-associated protein 2 (MRP2) transporters in Caco-2 cells. The data obtained from bidirectional transport studies in these cells indicate a clear involvement of P-gp but not of MRP2 in the transport of ximelagatran, hydroxy-melagatran, and melagatran across the apical cell membrane. The present study shows that short hairpin RNA Caco-2 cells are a valuable tool to investigate the contribution of specific transporters in the transcellular transport of drug molecules and to predict potential sites of pharmacokinetic interactions. The results also suggest that inhibition of hepatic P-gp is involved in the erythromycin-ximelagatran interaction seen in clinical studies.

Footnotes

  • This study was supported in part by a research grant from the Food and Drug Administration [Grant 1R43-FD003482-01].

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

    doi:10.1124/dmd.109.029967.

  • ABBREVIATIONS:

    DDI
    drug-drug interaction
    P-gp
    P-glycoprotein
    shRNA
    short hairpin RNA
    MDR1
    multidrug resistance 1
    MRP2
    multidrug resistance-associated protein 2
    HBSS
    Hanks' balanced salt solution
    BSP
    bromosulfophthalein
    HPLC
    high-performance liquid chromatography
    PCR
    polymerase chain reaction
    CT
    cycle threshold
    TEER
    transepithelial electrical resistance
    A
    apical
    B
    basolateral
    LC
    liquid chromatography
    siRNA
    small interfering RNA.

    • Received October 9, 2009.
    • Accepted December 18, 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

Investigation of the Involvement of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 in the Efflux of Ximelagatran and Its Metabolites by Using Short Hairpin RNA Knockdown in Caco-2 Cells

Malin Darnell, Johan E. Karlsson, Albert Owen, Ismael J. Hidalgo, Jibin Li, Wei Zhang and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2010, 38 (3) 491-497; DOI: https://doi.org/10.1124/dmd.109.029967

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Research ArticleArticle

Investigation of the Involvement of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 in the Efflux of Ximelagatran and Its Metabolites by Using Short Hairpin RNA Knockdown in Caco-2 Cells

Malin Darnell, Johan E. Karlsson, Albert Owen, Ismael J. Hidalgo, Jibin Li, Wei Zhang and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2010, 38 (3) 491-497; DOI: https://doi.org/10.1124/dmd.109.029967
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