Stereoselective analysis of fluvastatin in human plasma for pharmacokinetic studies

Fluvastatin, an inhibitor of cholesterol biosynthesis, is commercialized as a racemic mixture of the (+)-3R,5S and (-)-3S,5R sterecisomers, although i nhibition of HMG-CoA reductase mainly resides in the (+)-(3R,5S)-fluvastati n isomer. The aim of the present study was to analyze fluvastatin isomers i n human plasma with application to studies on kinetic disposition. Plasma s amples of I nil were eluted into 3 ml LC-18 Supelclean (Supelco) columns eq uilibrated with methanol and water. The columns were washed with water and acetonitrile and then eluted with methanol containing 0.2% diethylamine. Th e (+)-3R,5S and (-)-3S,5R isomers were separated by HPLC on a Chiralcel OD- H chiral phase column and detected by fluorescence (lambda (ex) 305 mn; lam bda (em) 390 nm). The quantification limit was 0.75 ng for each isomer/ml p lasma and linearity was observed up to 625 ng/ml. The relative standard dev iations obtained for intra- and inter-assay precision were lower than 10% a nd the recovery was higher than 80% for both enantiomers. Application of th e method to a stereoselective study on the pharmacokinetics of fluvastatin administered as a single oral dose (Lescol, 20 mg) to a healthy volunteer r evealed stereoselectivity, with the highest plasma concentrations being obs erved for the (-)-3S,5R isomer (C-max 92.4 vs. 60.3 ng/ml, AUC(0 - infinity ) 133.3 vs. 97.4 ng h/ml, Cl/f 150.2 vs. 205.2 1 h(-1) and V-d/f 4.4 vs. 6. 0 1/kg). (C) 2001 Elsevier Science B.V. All rights reserved.