Abstract

MDR1/ABCB1, MRP2/ABCC2, and breast cancer resistance protein (BCRP)/ABCG2 are expressed in the liver and intestine and contribute to the disposition of many drugs. Rosuvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor for the treatment of patients with dyslipidemia, is primarily excreted via bile as unchanged drug. The present study was designed to determine whether rosuvastatin is transported by MDR1, MRP2, and BCRP. The apparent permeability value for rosuvastatin across MDR1-Madin-Darby canine kidney cells was low (∼8 nm/s), and no directional transport was observed. Rosuvastatin uptake into control Sf9 membranes and membranes expressing MRP2 was similar in the presence or absence of GSH. In contrast, ATP dramatically stimulated rosuvastatin uptake into membranes expressing BCRP, but not control membranes. Rosuvastatin transport occurred into an osmotically sensitive space and was saturable. An Eadie-Hofstee analysis suggested that there were two transport sites in BCRP, with an apparent K_m of 10.8 μM for the high affinity site and 307 μM for the low affinity site. These data demonstrate that rosuvastatin is transported efficiently by BCRP and suggest that BCRP plays a significant role in the disposition of rosuvastatin.