Stereoselective analysis of metoprolol and its metabolites in rat plasma with application to oxidative metabolism.
We investigated the stereoselective kinetic disposition and metabolism of metoprolol (MET) in rats. The racemic MET (15 mg/kg) was given by oral gavage and blood samples were collected from 0 to 10h (n=6 at each time point). The enantiomeric concentrations of MET and its metabolites alpha-hydroxymetoprolol (alpha-OHM) and O-demethylmetoprolol (ODM) were determined by HPLC using a Chiralpak AD chiral column and fluorescence detection. The pharmacokinetic parameters of unchanged MET and the formation of ODM did not show to be stereoselective. In contrast, the AUC (ng h/mL) of alpha-hydroxymetoprolol isomers were higher to I'R [638.2(525.2-706.2) for 1'R2R and 659.6(580.4-698.1) for 1'R,2S, mean, (95%CI)] than to I'S products [58.3(47.4-66.1) for 1'S,2R and 57.1(44.7-67.9) for 1'S,2S, mean, (95%CI)]. We conclude that the kinetic disposition of unchanged MET and the formation of ODM are not enantioselective in rats but the metabolism of alpha-OHM yields predominantly the 1'R-product.
Boralli
Vanessa Bergamin
VB
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, Campus da USP, 14040-903 Ribeirão Preto, SP, Brazil.
Coelho
Eduardo Barbosa
EB
Cerqueira
Paula Macedo
PM
Lanchote
Vera Lucia
VL
D000319:Adrenergic beta-Antagonists / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D002942:Circular Dichroism; D006207:Half-Life; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; C029504:alpha-hydroxymetoprolol; C029502:O-demethylmetoprolol; D008790:Metoprolol