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MedLine Citation:
PMID:  21447733     Owner:  NLM     Status:  Publisher    
The objective of the present study was to determine the efflux transporters responsible for acid and lactone statin drugs efflux using transporter knockdown Caco-2 cells. The bidirectional transport was determined in Caco-2 cell monolayers in which the expression of either P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or multidrug resistance associated protein 2 (MRP2) was knocked down by transduction with targeted human lentivirus expression shRNA. Monolayers transduced with lentivirus containing non-targeted shRNA served as vector controls. Atorvastatin, lovastatin and rosuvastatin displayed extremely low apical-to-basolateral (A-B) transport, which made the P(app,A-B) values too unreliable to calculate the efflux ratio. Thus, transport comparisons were performed using the B-A permeability (P(app,B-A)) values. Presented in the order of vector control, P-gp, BCRP, and MRP2 knockdown Caco-2 cells, the P(app,B-A) values (×10(-6), cm/s) were 28.1±1.3, 8.6±2.9, 20.3±1.8 and 21.5±1.6 for atorvastatin; 96.1±7.1, 25.3±3.5, 57.3±9.8 and 48.2±2.3 for fluvastatin; 14.1±1.9, 4.6±1.7, 5.8±0.7 and 6.6±1.8 for rosuvastatin, respectively. Lovastatin and simvastatin showed no efflux in the vector control or knockdown cell monolayers in either lactone or acid forms. Results indicate that atorvastatin, fluvastatin and rosuvastatin were transported by P-gp, BCRP, and MRP2. On the other hand, neither the lactone nor the resulting acid forms of lovastatin and simvastatin were significantly transported by P-gp, BCRP or MRP2 in this cell system. The current study demonstrated that the transporter knockdown Caco-2 cells are useful tools for studying drug-transporter interactions and should help eliminate some of the ambiguity associated with the identification of drug-transporter interactions based on chemical inhibitors alone.
Jibin Li; Donna A Volpe; Ying Wang; Wei Zhang; Chris Bode; Albert Owen; Ismael J Hidalgo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-29
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Absorption Systems L.P.;
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