Pharmacokinetics of Metoprolol Enantiomers after Administration of the Racemate and the S-Enantiomer as Oral Solutions and Extended Release Tablets

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Plasma concentrations of S- and R-metoprolol were measured by an enantioselective assay method after single dosing of racemic metoprolol (metoprolol succinate 190mg) given as an oral solution and an extended release formulation in 12 healthy male subjects. Nine subjects were phenotyped as extensive metabolisers (EM) and 3 as poor metabolisers (PM) of metoprolol. The same subjects also received a single dose of enantiomerically pure S-metoprolol (S-metoprolol sorbate 110mg) in corresponding administration forms, providing fast and slow drug input.

The results confirmed stereoselective kinetics of metoprolol enantiomers in the EM subgroup, although there was no sign of such an effect in the 3 PMs. Stereoselectivity also appeared to be dependent on the drug input rate since the area under the concentration-time curve (AUC) ratio of S-metoprolol to R-metoprolol was higher in all 9 EM subjects after extended release administration compared with the oral solution of the racemate. There was no apparent difference in systemic clearance between the enantiomers as indicated by their similar elimination half-lives (2.8 hours for S- versus 2.6 hours for R-metoprolol).

In addition, the oral bioavailability of S-metoprolol was significantly lower after administration of the pure S-enantiomer solution than when the same dose of the S-form was given as the racemic solution [95% confidence interval (CI) for the AUC ratio was 61 to 81%]. Dose-dependent first-pass extraction and/or inhibition of the S-metoprolol metabolism by the R-form are suggested as possible causes of this difference. The reverse situation was seen when comparing the 2 extended release forms, although the difference in their AUCs was smaller (95% CI was 104 to 137%).

A possible therapeutic implication of the stereoselective properties of metoprolol is a somewhat greater pharmacological response in EMs following treatment with an extended release than following treatment with an immediate release preparation at the same total drug concentration. Furthermore, the differences in bioavailability of S-metoprolol imply that definition of therapeutically equivalent doses of racemic metoprolol and an enantiomerically pure formulation must be made on a formulation-by-formulation basis considering dissolution (input rate) characteristics and using enantioselective analysis in the pharmacokinetic evaluation.

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