PT - JOURNAL ARTICLE AU - Junichi Enokizono AU - Hiroyuki Kusuhara AU - Yuichi Sugiyama TI - Involvement of Breast Cancer Resistance Protein (BCRP/<em>ABCG2</em>) in the Biliary Excretion and Intestinal Efflux of Troglitazone Sulfate, the Major Metabolite of Troglitazone with a Cholestatic Effect AID - 10.1124/dmd.106.012567 DP - 2007 Feb 01 TA - Drug Metabolism and Disposition PG - 209--214 VI - 35 IP - 2 4099 - http://dmd.aspetjournals.org/content/35/2/209.short 4100 - http://dmd.aspetjournals.org/content/35/2/209.full SO - Drug Metab Dispos2007 Feb 01; 35 AB - 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. The American Society for Pharmacology and Experimental Therapeutics