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Research ArticleArticle

Estimation of Transporters Involved in the Hepatobiliary Transport of TA-0201CA Using Sandwich-Cultured Rat Hepatocytes from Normal and Multidrug Resistance-Associated Protein 2-Deficient Rats

Hajime Fukuda, Rikiya Ohashi, Noriko Ohashi, Hikaru Yabuuchi and Ikumi Tamai
Drug Metabolism and Disposition September 2010, 38 (9) 1505-1513; DOI: https://doi.org/10.1124/dmd.110.033258
Hajime Fukuda
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Rikiya Ohashi
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Noriko Ohashi
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Hikaru Yabuuchi
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Ikumi Tamai
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Abstract

N-[6-[2-[(5-Bromo-2-pyrimidinyl)oxy]ethoxy]-5-(4-methylphenyl)-4-pyrimidinyl]-4-(2-hydroxy-1,1-dimethylethyl) benzenesulfonamide sodium salt (TA-0201) carboxylic acid form (TA-0201CA) is the primary and pharmacologically active metabolite of TA-0201, which is an orally active nonpeptide antagonist for endothelin receptors. A major elimination route of TA-0201CA in rats was biliary excretion. The aim of this study was to clarify the transporters responsible for the hepatobiliary transport of TA-0201CA by in vivo pharmacokinetic study and in vitro study using sandwich-cultured rat hepatocytes (SCRH) from normal rats [Sprague-Dawley rats (SDR)] and Eisai hyperbilirubinemic rats (EHBR). After intravenous administration, TA-0201CA was extensively excreted into bile with a high biliary clearance in SDR. In contrast, the biliary clearance in EHBR was lower than that in SDR. These results indicated that multidrug resistance-associated protein 2 (Mrp2) was partly involved in the biliary excretion of TA-0201CA. In SCRH, the hepatic uptake of TA-0201CA was significantly decreased by the presence of organic anion-transporting polypeptide (Oatp) substrates/inhibitors and a Na+-free condition, which is a driving force of the Na+-taurocholate cotransporting polypeptide (Ntcp). The canalicular secretion of TA-0201CA was inhibited by the bile salt export pump (Bsep) inhibitor glibenclamide and by the Mrp2 inhibitor 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK-571) in SCRH from SDR and EHBR. These results suggested that TA-0201CA was transported into hepatocytes via Oatps and Ntcp and excreted into bile via Mrp2 and Bsep in rats.

Footnotes

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

    doi:10.1124/dmd.110.033258.

  • ABBREVIATIONS:

    NTCP/Ntcp
    Na+-taurocholate cotransporting polypeptide
    OATP/Oatp
    organic anion-transporting polypeptide
    OAT/Oat
    organic anion transporter
    OCT/Oct
    organic cation transporter
    BSEP/Bsep
    bile salt export pump
    MRP/Mrp
    multidrug resistance-associated protein
    BRCP/Bcrp
    breast cancer resistance protein
    MDR/Mdr
    multidrug resistance
    SCRH
    sandwich-cultured rat hepatocyte(s)
    TA-0201
    N-[6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-5-(4-methylphenyl)-4-pyrimidinyl]-4-(2-hydroxy-1,1-dimethylethyl) benzenesulfonamide sodium salt
    ET
    endothelin
    TA-0201CA
    TA-0201 carboxylic acid form
    SDR
    Sprague-Dawley rats
    EHBR
    Eisai hyperbilirubinemic rats
    DMEM
    Dulbecco's modified Eagle's medium
    HBSS
    Hanks' balanced salt solution
    FTC
    fumitremorgin C
    MK-571
    3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MOPS
    4-morpholinepropanesulfonic acid
    BEI
    biliary excretion index
    AUC
    area under the plasma concentration-time curve
    MRT
    mean residence time
    TEA
    tetraethylammonium.

  • Received March 14, 2010.
  • Accepted June 9, 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

Estimation of Transporters Involved in the Hepatobiliary Transport of TA-0201CA Using Sandwich-Cultured Rat Hepatocytes from Normal and Multidrug Resistance-Associated Protein 2-Deficient Rats

Hajime Fukuda, Rikiya Ohashi, Noriko Ohashi, Hikaru Yabuuchi and Ikumi Tamai
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1505-1513; DOI: https://doi.org/10.1124/dmd.110.033258

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Research ArticleArticle

Estimation of Transporters Involved in the Hepatobiliary Transport of TA-0201CA Using Sandwich-Cultured Rat Hepatocytes from Normal and Multidrug Resistance-Associated Protein 2-Deficient Rats

Hajime Fukuda, Rikiya Ohashi, Noriko Ohashi, Hikaru Yabuuchi and Ikumi Tamai
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1505-1513; DOI: https://doi.org/10.1124/dmd.110.033258
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