PHARMACOKINETICS OF METOPROLOL ENANTIOMERS AFTER ADMINISTRATION OF THE RACEMATE AND THE S-ENANTIOMER AS ORAL SOLUTIONS AND EXTENDED-RELEASETABLETS

Plasma concentrations of S- and R-metoprolol were measured by an enant ioselective assay method after single dosing of racemic metoprolol (me toprolol succinate 190mg) given as an oral solution and an extended re lease formulation in 12 healthy male subjects. Nine subjects were phen otyped as extensive metabolisers (EM) and 3 as poor metabolisers (PM) of metoprolol. The same subjects also received a single dose of enanti omerically pure S-metoprolol (S-metoprolol sorbate 110mg) in correspon ding administration forms, providing fast and slow drug input. The res ults confirmed stereoselective kinetics of metoprolol enantiomers in t he 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 ex tended release administration compared with the oral solution of the r acemate. There was no apparent difference in systemic clearance betwee n the enantiomers as indicated by their similar elimination half-lives (2.8 hours for S- versus 2.6 hours for R-metoprolol). In addition, th e oral bioavailability of S-metoprolol was significantly lower after a dministration of the pure S-enantiomer solution than when the same dos e of the S-form was given as the racemic solution [95% confidence inte rval (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-f orm are suggested as possible causes of this difference. The reverse s ituation was seen when comparing the 2 extended release forms, althoug h 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 foll owing 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 impl y that definition of therapeutically equivalent doses of racemic metop rolol and an enantiomerically pure formulation must be made on a formu lation-by-formulation basis considering dissolution (input rate) chara cteristics and using enantioselective analysis in the pharmacokinetic evaluation.