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, Ikumi Tamai

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1505-1513
Number of pages9
JournalDrug Metabolism and Disposition
Volume38
Issue number9
DOIs
Publication statusPublished - 09-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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