title: Key determinants of the circulatory exposure of organic anions: differences in hepatic uptake between multidrug resistance-associated protein 2 (Mrp2)-deficient rats and wild-type rats.
abstract: 1. Raloxifene-6-glucuronide (R6G) is a substrate of rat multidrug resistance-associated protein 2 (Mrp2), a transporter responsible for biliary excretion of organic anions. 2. Pharmacokinetic modeling of R6G in Eisai hyperbilirubinemic rats (EHBRs), hereditary Mrp2-deficient rats, and wild-type Sprague-Dawley rats (SDRs) indicated that reduction in not only biliary excretion but also hepatic uptake of R6G influenced low clearance in EHBRs. 3. An integration plot study demonstrated that the hepatic uptake of R6G was 66% lower in EHBRs than that in SDRs. A reduction was observed for the other Mrp2 substrate Valsartan (95% lower) but not for estradiol-17β-glucuronide (E217βG). This variation may be associated with the difference in substrate specificity of transporters and/or inhibition of hepatic uptake of organic anions by endogenous substances such as bilirubin glucuronides. 4. In conclusion, incidental alteration of the hepatic uptake of organic anions should be considered as an explanation of their enhanced systemic exposure in EHBRs.
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences , Chiba University Chiba , Japan and.
authors.forename: Keigo
authors.initials: K
authors.lastname: Kosaka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Susukida
authors.forename: Shigeki
authors.initials: S
authors.lastname: Aoki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kume
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D005965:Glucuronates / Q000493:pharmacokinetics* / Q000494:pharmacology; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000068756:Valsartan / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D005965:Glucuronates; D010880:Piperidines; C108482:raloxifene-6-beta-glucuronide; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D000068756:Valsartan
keywords: Eisai hyperbilirubinemic rat; integration plot; organic anion transporting polypeptide