title: Eisai hyperbilirubinemic rat (EHBR) as an animal model affording high drug-exposure in toxicity studies on organic anions.
abstract: The Eisai hyperbilirubinemic rat (EHBR) should be a useful animal model for studies on the toxicity of organic anions which are substrates of multidrug resistance-associated protein 2 (Mrp2), since the systemic exposure to these compounds is expected to be increased in EHBR. In this study, we tested the value of EHBR for this purpose, using pravastatin (PV) and methotrexate (MTX) as model compounds. In the case of a single oral dose of PV (200 mg/kg), C(max) in plasma was 4.0-fold higher and AUC(0-infinity) was 3.6-fold larger than those of normal Sprague-Dawley rats (SDR), respectively. When multiple doses of PV were given to EHBR without co-administration of any other compound, drug-induced skeletal muscle toxicity (myopathy/rhabdomyolysis) and increased creatine phosphokinase (CPK) level were observed, whereas a control experiment using SDR did not show any toxic change. When a single dose of MTX (0.6 mg/kg) was given to EHBR orally, C(max) was 1.7-fold higher and AUC(0-infinity) was 1.6-fold larger than those of SDR, respectively. When multiple doses of MTX were given to EHBR, the changes in bone marrow, spleen and intestines were more severe than those in SDR. These findings support the view that EHBR would be a valuable animal model for toxicity studies on organic anion compounds which are substrates of Mrp2.
authors.affiliation: Pharmaceutical Research Center, Mochida Pharmaceutical Co. Ltd., 722 Uenohara, Jimba. Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Naba
authors.forename: Chitose
authors.initials: C
authors.lastname: Kuwayama
authors.forename: Chihaya
authors.initials: C
authors.lastname: Kakinuma
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ohnishi
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000838:Anions / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D005493:Folic Acid Antagonists / Q000633:toxicity; D006207:Half-Life; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity; D006932:Hyperbilirubinemia / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000633:toxicity; D018482:Muscle, Skeletal / Q000201:enzymology; D017035:Pravastatin / Q000493:pharmacokinetics / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000838:Anions; D001798:Blood Proteins; D005493:Folic Acid Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase; D017035:Pravastatin; D008727:Methotrexate