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Received for publication September 21, 2004.
Revised December 6, 2004.
Accepted for publication December 14, 2004.
The purpose of this study is to examine the significance of efflux transporters in the small intestine to extrude glucuronide (G) and sulfate (S) conjugates into the intestinal lumen. From this standpoint, we performed in situ intestinal perfusion experiments by using Eisai hyperbilirubinemic rats (EHBR) in which the multidrug resistance protein 2 (Mrp2/Abcc2) is hereditarily defective and the breast cancer resistance protein (Bcrp1 / Abcg2) knock out mice. The intestinal lumen of EHBR and Bcrp1 (-/-) mice was perfused with medium containing 4-methylumbelliferone (4MU) and E3040 to determine the efflux of metabolites into the outflow. The efflux of E3040-G in EHBR was significantly lower compared with normal rats. However, no significant difference was observed for the efflux of 4MU-G, 4MU-S, and E3040-S between EHBR and normal rats. In contrast, the efflux of intracellularly formed 4MU-G, 4MU-S and E3040-G in Bcrp1 (-/-) mice was significantly lower than that in normal mice. Consequently, Bcrp1 has an important role in extruding glucuronide and sulfate conjugates formed in enterocytes into the intestinal lumen, whereas Mrp2 is responsible for the efflux of some glucuronide conjugates.
Key words:
MDR/p-Glycoprotein, Organic anion, Cytochrome P450, Phase II enzymes, Sulfotransferases, UDP-glucuronyltransferases
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