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Received for publication April 21, 2005.
Revised June 6, 2005.
Accepted for publication June 13, 2005.
Pitavastatin, a novel potent HMG-CoA reductase inhibitor, is selectively distributed to the liver and excreted into bile in unchanged form in rats. We previously reported that the hepatic uptake is mainly mediated by OATP1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with Km values of 5.73 µM and 4.77 µM, respectively. The biliary excretion clearance of pitavastatin in Bcrp1 (-/-) mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin unchanged between control and Eisai hyperbiliruminemic rats (EHBR), indicating minor contribution of Mrp2. This observation differs radically from that for a more hydrophilic statin, pravastatin of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the MDCK II cells expressing OATP1B1, and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.
Key words:
Organic anion, Liver transporters
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