Document Detail


Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin.
MedLine Citation:
PMID:  15901796     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 K(m) value of pravastatin for hBSEP was 124 muM. 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.
Authors:
Masaru Hirano; Kazuya Maeda; Hisamitsu Hayashi; Hiroyuki Kusuhara; Yuichi Sugiyama
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-05-18
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  314     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-18     Completed Date:  2005-09-30     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  876-82     Citation Subset:  IM    
Affiliation:
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / metabolism*
Adenosine Triphosphate / physiology
Adenoviridae / metabolism
Algorithms
Animals
Biological Transport, Active
Chemistry, Physical
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry,  metabolism*,  pharmacology
Kinetics
Physicochemical Phenomena
Pravastatin / chemistry,  metabolism*,  pharmacology
Rats
Taurocholic Acid / metabolism
Transport Vesicles / drug effects,  metabolism
Chemical
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Abcb11 protein, rat; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 56-65-5/Adenosine Triphosphate; 81-24-3/Taurocholic Acid; 81093-37-0/Pravastatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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