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.
Fukuda
Hajime
H
Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan.
Ohashi
Rikiya
R
Ohashi
Noriko
N
Yabuuchi
Hikaru
H
Tamai
Ikumi
I
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