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Research ArticleArticle

P-Glycoprotein-Mediated In Vitro Biliary Excretion in Sandwich-Cultured Rat Hepatocytes

Pieter P. Annaert, Ryan Z. Turncliff, Catherine L. Booth, Dhiren R. Thakker and Kim L. R. Brouwer
Drug Metabolism and Disposition October 2001, 29 (10) 1277-1283;
Pieter P. Annaert
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Ryan Z. Turncliff
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Catherine L. Booth
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Dhiren R. Thakker
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Kim L. R. Brouwer
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Abstract

Recently, sandwich-cultured (SC) rat hepatocytes have been used as an in vitro model to assess biliary excretion of drugs and xenobiotics. The purpose of the present study was to validate the use of SC rat hepatocytes for the in vitro assessment of P-glycoprotein (P-gp)-mediated biliary drug excretion. The specific and fluorescent P-gp substrate rhodamine 123 (Rh123) and the P-gp substrate digoxin were selected as model compounds. Rh123 and digoxin accumulation and Rh123 efflux under standard and Ca2+-free conditions were quantified in SC rat hepatocytes to determine substrate secretion into canalicular networks in vitro. The major role of P-gp in the biliary excretion of these compounds was confirmed by inhibition experiments with the potent P-gp inhibitor GF120918. Hepatocyte culture conditions, including media type and time in culture, significantly affected Rh123 biliary excretion. P-gp expression, as assessed by Western blot, was increased with culture time. Dexamethasone (an in vivo inducer of P-gp) concentrations ranging from 0.01 to 1 μM in the cell culture medium did not influence P-gp expression or Rh123 biliary excretion. Rh123 and digoxin biliary clearance values, predicted from SC rat hepatocyte data, were consistent with values reported in vivo and in isolated perfused rat liver studies. In conclusion, the results of this study demonstrate the utility of SC rat hepatocytes as an in vitro model to study and predict the biliary excretion of P-gp substrates.

Footnotes

  • This study was supported by National Institutes of Health Grant GM41935.

  • Abbreviations used are::
    IPRL
    isolated perfused rat liver
    SC
    sandwich-cultured
    P-gp
    P-glycoprotein
    Rh123
    rhodamine 123
    DMEM
    Dulbecco's modified Eagle's medium
    WEM
    Williams' E medium
    MCM
    modified Chee's medium
    BSA
    bovine serum albumin
    FBS
    fetal bovine serum
    ITS
    insulin-transferrin-selenium supplement
    HBSS
    Hanks' balanced salt solution
    BEI
    biliary excretion index
    MDR
    multidrug resistance
    • Received January 2, 2001.
    • Accepted June 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Research ArticleArticle

P-Glycoprotein-Mediated In Vitro Biliary Excretion in Sandwich-Cultured Rat Hepatocytes

Pieter P. Annaert, Ryan Z. Turncliff, Catherine L. Booth, Dhiren R. Thakker and Kim L. R. Brouwer
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1277-1283;

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Research ArticleArticle

P-Glycoprotein-Mediated In Vitro Biliary Excretion in Sandwich-Cultured Rat Hepatocytes

Pieter P. Annaert, Ryan Z. Turncliff, Catherine L. Booth, Dhiren R. Thakker and Kim L. R. Brouwer
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1277-1283;
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