Document Detail

Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics.
MedLine Citation:
PMID:  16697742     Owner:  NLM     Status:  MEDLINE    
BACKGROUND & AIMS: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, target liver HMG-CoA and are of proven benefit in the prevention of coronary heart disease. Rosuvastatin is an effective statin notable for liver selectivity and lack of significant metabolism. We assessed the extent and relevance of hepatic transporters to rosuvastatin uptake. METHODS: Transporters involved in rosuvastatin uptake were determined through heterologous expression of multiple human and rat uptake transporters. Human organic anion transporting polypeptide (OATP) 1B1 and sodium-dependent taurocholate cotransporting polypeptide (NTCP) allelic variants were also assessed. Expression of OATP and NTCP messenger RNA and protein was determined from a bank of human liver samples. RESULTS: Multiple OATP family members, including 1B1, 1B3, 2B1, and 1A2, were capable of rosuvastatin transport. Naturally occurring polymorphisms in OATP1B1, including *5, *9, *15, and *18, were associated with profound loss of activity toward rosuvastatin. Interestingly, the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp, also transported rosuvastatin. Human hepatocyte studies suggested that NTCP alone accounted for approximately 35% of rosuvastatin uptake. Remarkably, NTCP*2, a variant known to have a near complete loss of function for bile acids, exhibited a profound gain of function for rosuvastatin. Quantitative messenger RNA analysis revealed marked intersubject variability in expression of OATPs and NTCP. CONCLUSIONS: Multiple transporters mediate the overall hepatic uptake of rosuvastatin, and NTCP may be a heretofore unrecognized transporter important to the disposition of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, transporter expression and polymorphisms may be key determinants of intersubject variability in response to statin therapy in general.
Richard H Ho; Rommel G Tirona; Brenda F Leake; Hartmut Glaeser; Wooin Lee; Christopher J Lemke; Yi Wang; Richard B Kim
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-03-06
Journal Detail:
Title:  Gastroenterology     Volume:  130     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-05-15     Completed Date:  2006-06-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1793-806     Citation Subset:  AIM; IM    
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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MeSH Terms
Base Sequence
Biological Transport / drug effects
Cells, Cultured
Fluorobenzenes / pharmacokinetics,  pharmacology*
Gene Expression Regulation
Hepatocytes / cytology,  drug effects*
Molecular Sequence Data
Organic Anion Transporters, Sodium-Dependent / genetics,  metabolism*
Organic Anion Transporters, Sodium-Independent / genetics,  metabolism*
Pyrimidines / pharmacokinetics,  pharmacology*
RNA, Messenger / analysis
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Species Specificity
Sulfonamides / pharmacokinetics,  pharmacology*
Symporters / drug effects
Taurocholic Acid / pharmacology*
Grant Support
Reg. No./Substance:
0/Fluorobenzenes; 0/Organic Anion Transporters, Sodium-Dependent; 0/Organic Anion Transporters, Sodium-Independent; 0/Pyrimidines; 0/RNA, Messenger; 0/Sulfonamides; 0/Symporters; 287714-41-4/rosuvastatin; 81-24-3/Taurocholic Acid

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

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