title: Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123.
abstract: The hepatobiliary transport of an anionic cyclopentapeptide endothelin antagonist, BQ-123, was studied in rats. Biliary excretion of [3H]BQ-123 was extensive in vivo (approximately 75% of intravenous infusion rates). Liver-to-plasma and bile-to-liver concentration ratios at steady state were approximately 3 and 200, respectively, suggesting that hepatic uptake and biliary excretion are concentrative processes. The biliary excretion clearance exhibited a saturation at a hepatic concentration of > 100 nmol/g liver and was markedly reduced in Eisai hyperbilirubinemic rats, which have a hereditary defect of canalicular multispecific organic anion transporter. An ATP-dependent and saturable uptake of BQ-123 by isolated canalicular membrane vesicles was observed in vitro. Impaired transport of BQ-123 was also confirmed in canalicular membrane vesicles prepared from Eisai hyperbilirubinemic rats. These results demonstrate that the biliary excretion process is ATP-driven primary active transport. It is proposed that a canalicular multispecific organic anion transporter is mainly responsible for the biliary excretion of BQ-123.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: H C
authors.initials: HC
authors.lastname: Shin
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Niinuma
authors.forename: A
authors.initials: A
authors.lastname: Hisaka
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D001692:Biological Transport; D003470:Culture Media / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D006932:Hyperbilirubinemia / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains / Q000235:genetics; D012016:Reference Values; D013997:Time Factors
chemical_list: D003470:Culture Media; D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)