| Metoprolol (I) is a widely used beta-blocking agent used in the treatment of cardiovascular disorders. It is administered as a racemic mixture (R and S isomers) of metoprolol tartrate. Its pharmacokinetics in extensive metabolizing (EM) subjects is variable because of the extent of stereoselective oxidative first-pass metabolism to alpha-hydroxymetoprolol (II) diastereomers and an optically active acid (ACMB). Literature reports on the disposition of similar drugs suggested that differences in the disposition of S- and R-enantiomers may depend on input rate of drug delivered to the liver. Therefore, two clinical studies were conducted with EM subjects, aged 18--55 years, to determine if differences in the disposition of metoprolol enantiomers occur in humans when the input rate of metoprolol is altered.;The first clinical study was a four-way crossover study (seven subjects) with slow (S), moderate (M) and fast (F) extended release matrix-based metoprolol tartrate racemic 100 mg tablets with different release rates and a racemic 50 mg oral solution (Sol). The second study was (11 subjects) a two way parallel study using a racemic 100 mg metoprolol tartrate extended release tablet (A) and an encapsulated bead formulation (C). Plasma samples were assayed for total metoprolol and metabolites and their enantiomers by stereospecific and nonstereospecific high performance liquid chromatographic methods, specifically developed and validated for this purpose. The diastereomers of II, 1R2R and 1R2S, and 1S2S and 1S2R, were not chromatographically resolved and were seen as two peaks IIA and IIB, respectively. For all extended release formulations the amount of II, IIA and IIB formed were lower relative to the solution but all were equal for ACMB, R-ACMB and S-ACMB. The mean AUCinf ratio of the enantiomers (S/R) in all formulations ranged from 1.4--1.6 for I, from 1.3--1.4 for II and 0.9 for ACMB. Significant differences in S/R ratios were observed between absorption and the elimination phases for I, II and ACMB for the faster inputs (Sol and F) but no difference was observed for the slower inputs (S and C). The differences in rates of metabolism of drug enantiomers with varying input rates may have important clinical implications, because of an altered pharmacodynamic response. |
