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Research ArticleArticle

Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

Ebba Bergman, Anna Lundahl, Patrik Fridblom, Mikael Hedeland, Ulf Bondesson, Lars Knutson and Hans Lennernäs
Drug Metabolism and Disposition December 2009, 37 (12) 2349-2358; DOI: https://doi.org/10.1124/dmd.109.029363
Ebba Bergman
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Anna Lundahl
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Patrik Fridblom
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Mikael Hedeland
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Ulf Bondesson
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Lars Knutson
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Hans Lennernäs
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Abstract

The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 ± 3.5 and 35.7 ± 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUCbile/AUCVH ratio in TI of 1770 (1640–11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ± 0.06; TII, 0.46 ± 0.13) and increased the AUCVP and AUCVH by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.

Footnotes

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

    doi:10.1124/dmd.109.029363

  • DDI
    drug-drug interaction
    AUC
    area under the concentration-time curve
    OATP
    organic anion-transporting polypeptide
    NTCP
    human sodium-dependent taurocholate cotransporting polypeptide
    BCRP
    breast cancer resistance protein
    MRP2
    multidrug resistance-associated protein 2
    VH
    hepatic vein
    VP
    portal, vein
    VF
    femoral vein
    HLM
    human liver microsome
    PLM
    pig liver microsome
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    ESI
    electrospray ionization
    RSD
    relative standard deviation
    CI
    confidence interval
    i.j.
    intrajejunal.

    • Received July 7, 2009.
    • Accepted September 15, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (12)
Drug Metabolism and Disposition
Vol. 37, Issue 12
1 Dec 2009
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Research ArticleArticle

Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

Ebba Bergman, Anna Lundahl, Patrik Fridblom, Mikael Hedeland, Ulf Bondesson, Lars Knutson and Hans Lennernäs
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2349-2358; DOI: https://doi.org/10.1124/dmd.109.029363

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Research ArticleArticle

Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

Ebba Bergman, Anna Lundahl, Patrik Fridblom, Mikael Hedeland, Ulf Bondesson, Lars Knutson and Hans Lennernäs
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2349-2358; DOI: https://doi.org/10.1124/dmd.109.029363
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