Influência da inalação de metanol na farmacocinética enantiosseletiva da fluvastatina em ratos / Inalation influence of methanol on the pharmacokinetics enantiosselective of fluvastatin in rats.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Dislipidemia is one of the main causes of cardiovascular illness and very frequent in the adults population. Fluvastatin, a racemic mixture of the (-)-3S,5R and (+)-3R,5S enantiomers, has been shown to be a potent competitive inhibitor of HMGCoA reductase used in the hypercholesterolemia treatment and with elimination in the man essentially dependent of the CYP2C9. Methanol is used by solvent and is an inhibitor of the CYP2C9 in human beings. The present study reports the influence of methanol inhalation on the enantiosselective pharmacokinetics of fluvastatin in rats. Fluvastatin was administrated by oral gavage (5 mg/Kg) to the animals (n=6/time) and blood samples were collected until 30 hours. The enantiomers were analysed by HPLC using Chiralcel® OD-H column and fluorescence detection. The pharmacokinetics parameters were analysed by Wilcoxon and Mann-Witney tests. The results are reported as mean (95% CI). Kinetic disposition of FV for animals exposed to methanol (262mg/m3), as for control group, was enantiosselective with plasma accumulation of (-)-3S,5R enantiomer. The following differences (p<0.05) were observed between the control and methanol (1048 mg/m3), apparent total clearance (Cl/F) of 2.52 (1.64-3.40) vs 1.51 (1.01-2.06) L.h-1.Kg-1; apparent volume of distribution (Vd/F) of 44.60 (19.20-55.49) vs 10.45 (7.20-15.96) L.Kg-1; elimination half life (t1/2?) of 10.85 (5.92-14,47) vs 5.23 (4.22-6.27) h; elimination rate constant (?) of 0.06 (0.04-0.11) 0.13 (0.10-0.16) h-1, area under the plasma concentration versus time curve (AUC 0-?) of 991.79 (689.57-1491.00) vs 1647.20 (1155.30- 2391.60) ng.h.mL-1, and AUC(-)/AUC(+) 2.50 (2.03-4.06) vs 1.22 (0.96-1.56). The data demonstrated that methanol inhalation at 1048 mg/m3 results in loss of enantioselectivity with plasmatic accumulation of (+)-3R5S, modifying the enantioselective kinetic disposition of Fluvastatin in rats.

ASSUNTO(S)

pharmacokinetics fluvastatin fluvastatina enantiomers metanol enantiômeros farmacocinética. methanol

ACESSO AO ARTIGO

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