AGING AND THE PHARMACOKINETICS AND METABOLISM OF METOPROLOL ENANTIOMERS IN THE RAT

After i. v. administration of racemic metoprolol in the rat, the plasm a concentrations of (R)- and (S)-metoprolol were comparable, and no di fferences in pharmacokinetic parameters between the two enantiomers we re found. From the 3rd to the 12th month, comparable changes were seen for both enantiomers: there was an increase in the area under the pla sma concentration-time curve (AUC) and a decrease in blood and plasma clearance. Half-life showed a significant prolongation, volume of dist ribution decreased between 3 and 12 months and increased between 12 an d 24 months. After oral administration of the racemate, AUC and C(max) (maximum plasma concentration) were slightly higher, while oral clear ance was slightly lower for (R)-metoprolol than for (S)-metoprolol. Wi th aging, C(max) and AUC increased for both enantiomers, while oral cl earance decreased. The change in oral clearance as a function of age i s different between (S)- and (R)-metoprolol, and thus enantioselective . In vitro disappearance rate in 3-month-old rats was significantly hi gher for (S)-metoprolol than for (R)-metoprolol, although the differen ce was small. With aging, the disappearance rates of both enantiomers increased significantly, but not enantioselectively.