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HMG‐CoA reductase inhibitors and P‐glycoprotein modulation
Author(s) -
Bogman Katrijn,
Peyer AnneKathrin,
Török Michael,
Küsters Ernst,
Drewe Jürgen
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703920
Subject(s) - fluvastatin , pravastatin , simvastatin , lovastatin , atorvastatin , chemistry , hmg coa reductase , reductase , pharmacology , biochemistry , rhodamine 123 , p glycoprotein , enzyme , cholesterol , biology , multiple drug resistance , antibiotics
Five 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P‐glycoprotein (P‐gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over‐expresses the multi‐drug resistance protein 1a/b (mdr1a/1b). P‐gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration‐dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P‐gp and results were comparable for both methods. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P‐gp affinity in drug screening that is especially useful for early phases of drug development.British Journal of Pharmacology (2001) 132 , 1183–1192; doi: 10.1038/sj.bjp.0703920