Stereospecific disposition of fluvastatin in streptozotocin-induced diabetic rats

Abstract

The study reports on the stereoselective pharmacokinetics of fluvastatin, a racemic mixture of (–)-(3S,5R)- and (+)-(3R,5S)-enantiomers, in streptozotocin-induced diabetic rats. Wistar (control) and streptozotocin-induced diabetic rats (n = 6/time point) received by oral gavage racemic fluvastatin (5 mg/kg), and blood samples were collected until 24 h. The enantiomers were analysed by chiral HPLC with fluorescence detection. The pharmacokinetic parameters were analysed by Wilcoxon and Mann–Whitney tests. The results are reported as means (95% CI). The following differences (p < 0.05) were observed between the control and diabetic groups, respectively: maximum plasma concentration (Cmax) of (–)-(3S,5R), 410.0 (310.0–510.0) versus 532.6 (463.5–601.8) ng·mL–1; area under the plasma concentration versus time curve (AUC0–[Formula: see text]) for (–)-(3S,5R), 4342.4 (3775.7–4909.0) versus 3025.2 (2218.9–3831.5) ng·h·mL–1; apparent total clearance (Cl/f) of (–)-(3S,5R), 0.6 (0.5–0.7) versus 0.9 (0.6–1.1) L·h–1·kg–1; AUC0–[Formula: see text] for (+)-(3R,5S), 493.5 (376.9–610.1) versus 758.5 (537.1–980.0) ng·h·mL–1; and Cl/f of (+)-(3R,5S), 5.3 (3.9–6.8) versus 3.5 (2.6-4.4) L·h–1·kg–1. Streptozotocin-induced diabetes in rats alters the pharmacokinetics of fluvastatin in a stereoselective manner. Key words: fluvastatin, enantiomers, pharmacokinetics, rats, streptozotocin diabetes.