Plasma concentrations ofS- andR-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 pureS-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 ofS-metoprolol toR-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 forS- versus 2.6 hours forR-metoprolol).In addition, the oral bioavailability ofS-metoprolol was significantly lower after administration of the pureS-enantiomer solution than when the same dose of theS-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 theS-metoprolol metabolism by theR-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 ofS-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.