Am. Vermeulen et al., AGING AND THE PHARMACOKINETICS AND METABOLISM OF METOPROLOL ENANTIOMERS IN THE RAT, Journal of gerontology, 48(3), 1993, pp. 108-114
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.