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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of 5 (and 6)-Carboxy-2′,7′-Dichlorofluorescein and Its Diacetate Promoiety in the Liver

Maciej J. Zamek-Gliszczynski, Hao Xiong, Nita J. Patel, Ryan Z. Turncliff, Gary M. Pollack and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics February 2003, 304 (2) 801-809; DOI: https://doi.org/10.1124/jpet.102.044107
Maciej J. Zamek-Gliszczynski
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Hao Xiong
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Nita J. Patel
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Ryan Z. Turncliff
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Gary M. Pollack
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Kim L. R. Brouwer
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Abstract

Hepatic disposition of 5 (and 6)-carboxy-2′,7′-dichlorofluorescein (CDF) and its diacetate promoiety (CDFDA) was studied in isolated perfused rat livers. Livers from Wistar wild-type and multidrug resistance-associated protein (Mrp)2-deficient (TR−) rats were perfused with CDF in the presence or absence of probenecid. Probenecid decreased the recovery of CDF in bile ∼4-fold in wild-type livers (65 ± 8% versus 15 ± 2% of dose over 2 h). In livers from TR− rats, CDF was not excreted into bile and probenecid decreased perfusate CDF concentrations in a concentration-dependent manner, in part due to inhibition of Mrp3. Plasma membrane vesicles from rat Mrp2- or Mrp3-transfected Sf9 cells were used to confirm that CDF is a substrate for Mrp2 and Mrp3; probenecid inhibited the transport of CDF by Mrp2 and Mrp3 in a concentration-dependent manner. CDF uptake in collagen sandwich-cultured rat hepatocytes was temperature-dependent and saturable (Km = 22 ± 10 μM;Vmax = 97 ± 9 pmol/min/mg protein). Uptake of CDF in sandwich-cultured rat hepatocytes was impaired significantly by bromosulfophthalein, a substrate for organic anion-transporting polypeptides (Oatps), but was not modulated by specific Oatp2 or organic anion transporter (Oat) substrates. CDFDA uptake was not saturable, temperature-dependent, or impaired by inhibitors. The hydrolysis of CDFDA to CDF is mediated by basic pH and esterases in biological media. CDFDA passively diffuses into hepatocytes where it is hydrolyzed to CDF. In contrast, CDF appears to be taken up by Oatp-mediated transport into rat hepatocytes and effluxed via Mrp2 into bile and via Mrp3 into sinusoidal blood.

Footnotes

  • This research was supported by National Institutes of Health Grant GM41935. M.J.Z.-G. was supported by a Research Fellowship in Pharmaceutics from the Pharmaceutical Research and Manufacturers of America Foundation.

  • DOI: 10.1124/jpet.102.044107

  • Abbreviations:
    CDF
    5 (and 6)-carboxy-2′,7′-dichlorofluorescein
    CDFDA
    5 (and 6)-carboxy-2′,7′-dichlorofluorescein diacetate
    Mrp
    multidrug resistance-related protein
    TR− rats
    Mrp2-deficient rats
    HBSS
    Hanks' balanced salt solution
    GFP
    green fluorescence protein
    Oatp
    organic anion-transporting polypeptide
    Oat
    organic anion transporter
    • Received September 5, 2002.
    • Accepted October 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 2
1 Feb 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of 5 (and 6)-Carboxy-2′,7′-Dichlorofluorescein and Its Diacetate Promoiety in the Liver

Maciej J. Zamek-Gliszczynski, Hao Xiong, Nita J. Patel, Ryan Z. Turncliff, Gary M. Pollack and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 801-809; DOI: https://doi.org/10.1124/jpet.102.044107

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of 5 (and 6)-Carboxy-2′,7′-Dichlorofluorescein and Its Diacetate Promoiety in the Liver

Maciej J. Zamek-Gliszczynski, Hao Xiong, Nita J. Patel, Ryan Z. Turncliff, Gary M. Pollack and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics February 1, 2003, 304 (2) 801-809; DOI: https://doi.org/10.1124/jpet.102.044107
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