title: Involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion and intestinal efflux of troglitazone sulfate, the major metabolite of troglitazone with a cholestatic effect.
abstract: Troglitazone sulfate (TGZS) is the major metabolite of troglitazone (TGZ), an antidiabetic agent, and thought to be a cause of the cholestasis induced by TGZ. The aim of the present study is to elucidate the involvement of breast cancer resistance protein (BCRP/ABCG2) in the hepatic disposition of TGZS. The basal-to-apical transport of TGZS was enhanced in organic anion transporting polypeptide 1B1-expressing Madin-Darby canine kidney II cells by infection of recombinant adenovirus harboring human BCRP and mouse Bcrp cDNA. TGZS was given to wild-type and Bcrp (-/-) mice by constant infusion. Biliary excretion is the predominant elimination pathway of TGZS in wild-type mice, and the biliary excretion clearance of TGZS with regard to the hepatic concentration was reduced to 30% of the control in Bcrp (-/-) mice. However, plasma and hepatic concentrations were unchanged, suggesting induction of compensatory mechanisms in Bcrp (-/-) mice for the elimination of TGZS. Involvement of BCRP in the intestinal efflux transport of TGZS was examined using everted sacs. The mucosal efflux clearance of TGZS showed only a slight reduction (15% reduction) in Bcrp (-/-) mice. Our results suggest that BCRP plays a major role in the biliary excretion but a minor role in the intestinal transport of TGZS.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Enokizono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced*; D002839:Chromans / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D027361:Organic Anion Transporters / Q000502:physiology; D045162:Thiazolidinediones / Q000378:metabolism*; D000077288:Troglitazone
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002839:Chromans; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D045162:Thiazolidinediones; D000077288:Troglitazone