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Research ArticleArticle

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Rune Amundsen, Hege Christensen, Behnaz Zabihyan and Anders Åsberg
Drug Metabolism and Disposition September 2010, 38 (9) 1499-1504; DOI: https://doi.org/10.1124/dmd.110.032268
Rune Amundsen
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Hege Christensen
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Behnaz Zabihyan
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Anders Åsberg
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Abstract

The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 (OATP1B1) in vitro. Patients with solid organ transplants are frequently treated with HMG-CoA reductase inhibitors (statins). CsA increases atorvastatin systemic exposure severalfold, an effect not observed with Tac. The effect of CsA and Tac on atorvastatin transport via OATP1B1 was investigated in transfected human embryonic kidney 293 cells. An in vitro-in vivo extrapolation (IVIVE) was performed to estimate the clinical potential for CsA and Tac to inhibit OATP1B1-mediated transport. CsA inhibited OATP1B1-mediated uptake of atorvastatin approximately 90-fold more efficiently than Tac, with half-maximal inhibitory concentration (IC50) values of 0.021 ± 0.004 and 1.99 ± 0.42 μM, respectively. Coincubation compared with preincubation with CsA showed a 20-fold lower inhibitory capacity, with an IC50 value of 0.47 ± 0.34 μM. The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC50 value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.

Footnotes

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

    doi:10.1124/dmd.110.032268.

  • ABBREVIATIONS:

    CsA
    cyclosporine A
    P-gp
    P-glycoprotein
    OATP
    organic anion-transporting polypeptide
    Tac
    tacrolimus
    HEK
    human embryonic kidney
    DMEM
    Dulbecco's modified Eagle's medium
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry.

  • Received January 15, 2010.
  • Accepted June 1, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Rune Amundsen, Hege Christensen, Behnaz Zabihyan and Anders Åsberg
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1499-1504; DOI: https://doi.org/10.1124/dmd.110.032268

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Research ArticleArticle

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Rune Amundsen, Hege Christensen, Behnaz Zabihyan and Anders Åsberg
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1499-1504; DOI: https://doi.org/10.1124/dmd.110.032268
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