Influência do etilbenzeno na farmacocinética enantiosseletiva do metoprolol em ratos

Abstract

GRACIANI, F. S. Influence of ethylbenzene on the enantioselective pharmacokinetics of metoprolol in rats. 2009. 77f. Dissertation (Master). Faculdade de Ciencias Farmaceuticas de Ribeirao Preto – Universidade de Sao Paulo, Ribeirao Preto, 2009. Metoprolol is mainly metabolized by CYP3A and CYP2D and ethylbenzene is an inducer of CYP3A in rats. In view of these considerations, the objective of the present study was to investigate the influence of low-level inhalation exposure to ethylbenzene on the kinetic disposition and metabolism of metoprolol enantiomers. Male Wistar rats were received a single dose of 15 or 30 mg/kg racemic metoprolol by gavage. The animals were divided into 4 groups: two control groups (15 and 30 mg/kg) and two groups exposed to ethylbenzene at concentrations of 434 and 1736 mg/m. The animals were exposed to ethylbenzene in a nose-only exposure chamber for 6 h/day during 5 consecutive days. Serial blood samples (n=6 animals per sampling time) were collected during the first 6 h after metoprolol administration. The isomers of metoprolol and its metabolites were analyzed in plasma samples by highperformance liquid chromatography with fluorescence detection. Pharmacokinetic analysis was performed using a two-compartment model. Metoprolol administered at a dose of 30 mg/kg showed nonlinear pharmacokinetics, with plasma accumulation of both metoprolol enantiomers and a reduction in the clearance of R-(+)-metoprolol (39.91 vs 78.37 L/h/kg) when compared to the group receiving the dose of 15 mg/kg. The kinetic disposition of the enantiomers of metoprolol administered at a dose of 15 mg/kg was linear and non-enantioselective. Exposure to 434 mg/m ethylbenzene did not influence the pharmacokinetics of either metoprolol enantiomer. Exposure to 1736 mg/m ethylbenzene increased the clearance of both metoprolol enantiomers by approximately 300% (224.66 vs 78.37 L/h/kg and 213.62 vs 73.63 L/h/kg for the R(+)and S-(-)-metoprolol enantiomer, respectively). These changes in clearance might be explained by an increase in the formation of the enantiomers of the two metabolites O-demethylmetoprolol (AUC: 122.84 vs 61.57 ng/h/mL and 92.33 vs 58.56 ng/h/mL for the R-(+)and S-(-)enantiomer, respectively) and Odemethylmetoprolol acid (AUC: 8592.0 vs 6812.5 ng/h/mL and 8733.0 vs 6787.0 ng/h/mL). In conclusion, inhalation exposure of rats to ethylbenzene at a concentration of 1736 mg/m for 5 days, 6 h per day, resulted in the nonenantioselective induction of the metabolism of metoprolol.