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 10 h (n = 6 at each time point). The enantiomeric concentrations of MET and its metabolites α-hydroxymetoprolol (α-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 α-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 α-OHM yields predominantly the 1′R-product.