Abstract
The bile salt export pump (BSEP/Bsep/ABCB11) and multidrug resistance‐associated protein 2 (MRP2/Mrp2/ABCC2) are involved in bile acid‐dependent and ‐independent bile secretion, respectively. It has been reported that bosentan, an endothelin receptor antagonist, inhibits Bsep, which may lead to cholestatic liver injury due to the intracellular accumulation of bile salts, while increasing bile salt‐independent bile flow. Thus, in this study, the effects of bosentan on BSEP/Bsep and MRP2/Mrp2 were evaluated using membrane vesicles derived from Spodoptera frugiperda (Sf) 9 cells, which express these transporters. The adenosine 5′‐triphosphate (ATP)‐dependent uptake of ^3^H‐taurocholic acid into membrane vesicles for BSEP/Bsep was inhibited by bosentan, and its IC~50~ values were 76.8 and 101 µM for BSEP and Bsep, respectively. In contrast, bosentan stimulated the MRP2/Mrp2‐mediated ATP‐dependent vesicular transport of ^3^H‐estradiol 17β‐glucuronide by shifting the sigmoidal dependence of transport rate on substrate concentration to a more hyperbolic one. Collectively, these results suggest that bosentan inhibits BSEP in humans with a similar potency to rats, and that increased bile salt‐independent flow in rats by bosentan is at least partly attributable to the activation of Mrp2. Copyright © 2006 John Wiley & Sons, Ltd.