Abstract
Pravastatin is a well known 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. Cumulative studies have shown that pravastatin is taken up into hepatocytes by the organic anion transporting polypeptide family transporters and excreted into the bile as an intact form by multidrug resistance-associated protein 2 (MRP2). It is generally accepted that the bile salt export pump (BSEP/ABCB11) mainly transports bile acids and plays an indispensable role in their biliary excretion. Interestingly, we found that BSEP could accept pravastatin as a substrate. Significant ATP-dependent uptake of pravastatin by human BSEP (hBSEP)- and rat BSEP (rBsep)-expressing membrane vesicles was observed, and the ratio of the uptake activity of pravastatin to that of taurocholic acid (TCA) by hBSEP was 3.3-fold higher than that by rBsep. The Km value of pravastatin for hBSEP was 124 μM. A mutual inhibition study between TCA and pravastatin revealed that they competitively interact with hBSEP. Several statins inhibited the hBSEP- and rBsep-mediated uptake of TCA; however, the specific uptake of other statins (cerivastatin, fluvastatin, and pitavastatin) by hBSEP and rBSEP was not detected. The inhibitory effects of hydrophilic statins (pravastatin and rosuvastatin) on the uptake of TCA by BSEP were relatively lower than those of lipophilic statins. These data suggest that BSEP may be partly involved in the biliary excretion of pravastatin in both rats and humans.
Footnotes
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This work was supported by Health and Labor Sciences Research grants from the Ministry of Health, Labor, and Welfare for the Research on Advanced Medical Technology and Grant-in-Aid for Young Scientists B 15790087 from the Ministry of Education, Culture, Sports, Science and Technology.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.084830.
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ABBREVIATIONS: ABC, ATP-binding cassette; MRP/Mrp, multidrug resistance-associated protein; BSEP/bsep, bile salt export pump; OATP/Oatp, organic anion transporting polypeptide; EHBR, Eisai hyperbiliruminemic rat; SDR, Sprague-Dawley rat; CMV, canalicular membrane vesicle; E1S, estrone-3-sulfate; TCA, taurocholic acid; MTX, methotrexate; hBSEP, human bile salt export pump; rBsep, rat bile salt export pump; GFP, green fluorescent protein; HEK, human embryonic kidney.
- Received February 11, 2005.
- Accepted May 16, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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