title: Hepatobiliary transport of YM466, a novel factor Xa inhibitor, in rats.
abstract: YM466, a novel factor Xa inhibitor, is a hydrophilic compound with a carboxylic acid moiety. Previous studies in rats have shown that YM466 does nor undergo metabolism but is excreted into the bile and urine in unchanged form. Thus, in this study, we investigated in vivo hepatobiliary transport, focusing in particular on multidrug resistance-associated protein 2 (Mrp2/Abcc2)-mediated transport. The hepatobiliary transport of YM466 was investigated after its systemic infusion into Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), which lack Mrp2. When the binding of YM466 in the plasma and liver was examined, the bile-to-plasma concentration ratio and the liver-to-plasma concentration ratio for the unbound concentration in SDRs amounted to 32.2 and 2.83, respectively, suggesting concentrated transport. The bile-to-liver concentration ratio for the unbound concentration in EHBRs was not lower than that found for SDRs. These findings suggest that YM466 is excreted from the plasma into the bile in a concentrated manner; however, Mrp2 does not play a major role in biliary excretion.
authors.affiliation: Drug Metabolism Research Laboratories, Astellas Pharma Inc., Itabashi-ku, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mano
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism*; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009281:Naphthalenes; D010880:Piperidines; C111032:YM 60828