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Drug Metabolism and Disposition Fast Forward
First published on November 8, 2006; DOI: 10.1124/dmd.106.012567

0090-9556/07/3502-209-214$20.00
DMD 35:209-214, 2007

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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

Junichi Enokizono, Hiroyuki Kusuhara, and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

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.

Address correspondence to: Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp




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J. Enokizono, H. Kusuhara, A. Ose, A. H. Schinkel, and Y. Sugiyama
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J. Enokizono, H. Kusuhara, and Y. Sugiyama
Regional Expression and Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Mouse Intestine: Overlapping Distribution with Sulfotransferases
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