Influence of input rate on the stereospecific and nonstereospecific first pass metabolism and pharmacokinetics of metoprolol extended release formulations

The purpose of this study was to examine the influence of input rate on the stereoselective and nonstereoselective pharmacokinetics of metoprolol, alpha-hydroxymetoprolol, and its acid metabolite. Extended release formulations (100 mg) of metoprolol with varying release rates (e.g., slow (S), moderate (M), and fast (F)) and an oral solution (OS, 50 mg) were administered to normal, healthy extensive metabolizers. Serial blood samples were collected over 48 h, plasma was obtained, and subsequently analyzed by a validated HPLC method with fluorescence detection. The mean T(max) of metoprolol after the S, M, F (4.43, 4.00, 3.14 h, respectively) was found to be different ( P < 0.05) as compared to the OS (2.07 h). The ratio of alpha-hydroxymetoprolol/metoprolol was higher for the OS (1.26) vs. the S, M, and F (1.02, 0.96, 0.99). The S/R enantiomer ratios of the concentration for metoprolol, ACMB, and alpha-hydroxmetoprolol were calculated at each time point and showed a significant difference ( P < 0.05) in the absorption phase (1-4 h) vs. terminal phase (8-16 h) for fast input (solution and fast extended release formulations). Based on these results, it would appear that input rate influences the pharmacokinetics of metoprolol, its metabolites, and their enantiomers.