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.
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.
Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan.
Hajime
H
Fukuda
Rikiya
R
Ohashi
Noriko
N
Ohashi
Hikaru
H
Yabuuchi
Ikumi
I
Tamai
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*
D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C113972:T 0201