title: Troglitazone metabolism and transporter effects in chimeric mice: a comparison between chimeric humanized and chimeric murinized FRG mice.
abstract: 1. The biotransformation, hepatic transporter and blood chemistry effects of troglitazone were investigated following 7 days of dosing at 600 mg/kg/day to chimeric murinized or humanized FRG mice, Mo-FRG and Hu-FRG mice, respectively. 2. Clinical chemistry and histopathology analysis revealed a significant drop in humanization over the time course of the study for the Hu-FRG mice but no significant changes associated with troglitazone treatment in either the Mo-FRG or the Hu-FRG models. No changes in transporter expression in livers of these mice were observed. Oxidative and conjugative metabolic pathways were identified with a 15- to 18-fold increase in formation of troglitazone sulfate in the Hu-FRG mice compared with the Mo-FRG mice in blood and bile, respectively. This resembles the troglitazone metabolism in human and these data are comparable with the formation of this metabolite in the chimeric uPA(+/+)/SCID mice. 3. However, larger amounts of troglitazone glucuronide were also observed in the Hu-FRG mouse compared with the Mo-FRG mouse which may be an effect of the drop in humanization of the Hu-FRG mouse during the study. 4. Highly humanized mice have a considerable potential in providing a useful first insight into circulating human metabolites of candidate drugs metabolized in the liver.
authors.affiliation: RIA iMED DMPK, AstraZeneca , Mölndal , Sweden .
authors.forename: Kristin
authors.initials: K
authors.lastname: Samuelsson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.forename: Sunil
authors.initials: S
authors.lastname: Sarda
authors.forename: John R
authors.initials: JR
authors.lastname: Foster
authors.forename: Kevin
authors.initials: K
authors.lastname: Randall
authors.forename: Anna
authors.initials: A
authors.lastname: Abrahamsson
authors.forename: Matt
authors.initials: M
authors.lastname: Jacobsen
authors.forename: Lars
authors.initials: L
authors.lastname: Weidolf
authors.forename: Ian
authors.initials: I
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001774:Blood Chemical Analysis; D002839:Chromans / Q000378:metabolism* / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D013463:Sulfuric Acid Esters / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism* / Q000493:pharmacokinetics*; D018183:Transplantation Chimera; D000077288:Troglitazone
chemical_list: D002839:Chromans; D026901:Membrane Transport Proteins; D013463:Sulfuric Acid Esters; D045162:Thiazolidinediones; C549564:troglitazone sulfate; D006867:Hydrolases; C020156:fumarylacetoacetase; D000077288:Troglitazone