Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers

Abstract

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in 6 extensive (EM) and 6 poor (PM) debrisoquin metabolizers. In EM, plasma AUC [area under the concentration-time curve] for (S)-metoprolol were 35% higher than for (R)-metoprolol, whereas in PM, AUC for (S)-metoprolol were lower than for (R)-metoprolol. AUC for total metoprolol correlated with the ratio if (S)- to (R)-metoprolol AUC. The renal clearance of metoprolol was stereoselective but to the same extent in both EM and PM. The enzyme system responsible for polymorphic oxidation of the debrisoquin-type is apparently stereoselective. The relation between log total metoprolol plasma concentration and response (.beta.-blockade) was shifted to the right in PM relative to EM, which is compatible with a difference in pharmacologic activity of metoprolol enantiomers. Kinetic predictions based on total drug measurements will tend to overestimate dynamic differences between EM and PM, but the magnitude of the error is relatively small, and, in absolute terms, there is a large difference in pharmacologic activity between the phenotypes (.beta.-blockade at 24 h: EM = 5.3 .+-. 5.6% and PM = 18.9 .+-. 3.8%).