Received for publication August 28, 2006.
Revised November 1, 2006.
Accepted for publication November 1, 2006.

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, an anti-diabetic agent, and thought to be a cause of the cholestasis induced by troglitazone (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 OATP1B1 expressing MDCK II cells by infection of recombinant adenovirus harbouring hBCRP and mBcrp 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.

Key words: ABC transporters, absorption, drug efflux, drug transport, hepatic elimination, hepatic transport, hepatobiliary disposition, hepatobiliary transport, transporters