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.
Footnotes
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This study was supported by Health and Labour Sciences Research Grants for Research on Regulatory Science of Pharmaceuticals and Medical Devices from Ministry of Health, Labour, and Welfare for the Research on Advanced Medical Technology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012567.
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ABBREVIATIONS: TGZ, troglitazone; TGZS, troglitazone sulfate; BSEP, bile salt excrete pump; SULT, sulfotransferase; OATP, organic anion transporting polypeptide; MRP2/Mrp2, multidrug resistance-associated protein 2; BCRP/Bcrp, breast cancer resistance protein; ME3277, sodium hydrogen {4-[(4,5,6,7-tetrahydrothieno {3,2-c} pyridin-2-yl) carbonylamino] acetyl-o-phenylene} dioxydiacetate; MDCKII, Madin-Darby canine kidney II; GFP, green fluorescent protein; mBcrp, mouse Bcrp; hBCRP, human BCRP; PBS, phosphate-buffered saline; LC/MS, liquid chromatography/mass spectrometry; BSA-KRB, bovine serum albumin/Krebs-Ringer bicarbonate; SNP, single nucleotide polymorphism(s).
- Received August 27, 2006.
- Accepted November 1, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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