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 ( approximately 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 muM for the high affinity site and 307 microM 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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / biosynthesis
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ATP-Binding Cassette Transporters / genetics
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Adenosine Triphosphate / physiology*
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Biological Transport, Active
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Cytoplasmic Vesicles / metabolism
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Drug Resistance, Neoplasm*
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Female
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Fluorobenzenes / metabolism*
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Humans
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Kinetics
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Mitochondrial Proteins / biosynthesis
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Mitochondrial Proteins / genetics
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Multidrug Resistance-Associated Protein 2
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Pyrimidines / metabolism*
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Ribosomal Proteins / biosynthesis
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Ribosomal Proteins / genetics
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Rosuvastatin Calcium
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Saccharomyces cerevisiae Proteins / biosynthesis
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Saccharomyces cerevisiae Proteins / genetics
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Subcellular Fractions / metabolism
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Sulfonamides / metabolism*
Substances
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ABCC2 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Fluorobenzenes
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MRP2 protein, S cerevisiae
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Mitochondrial Proteins
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Multidrug Resistance-Associated Protein 2
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Neoplasm Proteins
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Pyrimidines
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Ribosomal Proteins
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Saccharomyces cerevisiae Proteins
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Sulfonamides
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Rosuvastatin Calcium
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Adenosine Triphosphate