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 stereoisomers, although inhibition of HMG-CoA reductase mainly resides in the (+)-(3R,5S)-fluvastatin isomer. The aim of the present study was to analyze fluvastatin isomers in human plasma with application to studies on kinetic disposition. Plasma samples of 1 ml were eluted into 3 ml LC-18 Supelclean (Supelco) columns equilibrated with methanol and water. The columns were washed with water and acetonitrile and then eluted with methanol containing 0.2% diethylamine. The (+)-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 nm; lambda(em) 390 nm). The quantification limit was 0.75 ng for each isomer/ml plasma and linearity was observed up to 625 ng/ml. The relative standard deviations obtained for intra- and inter-assay precision were lower than 10% and the recovery was higher than 80% for both enantiomers. Application of the method to a stereoselective study on the pharmacokinetics of fluvastatin administered as a single oral dose (Lescol, 20 mg) to a healthy volunteer revealed stereoselectivity, with the highest plasma concentrations being observed for the (-)-3S,5R isomer (Cmax 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 l h(-1) and Vd/f 4.4 vs. 6.0 l/kg).
Lanchote
V L
VL
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, SP, Brazil. lanchote@fcfrp.usp.br
Rocha
A
A
de Albuquerque
F U
FU
Coelho
E B
EB
Bonato
P S
PS
D000328:Adult; D000924:Anticholesteremic Agents / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D005229:Fatty Acids, Monounsaturated / Q000097:blood* / Q000493:pharmacokinetics; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D007211:Indoles / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin