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1 The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. 2 The loglo metoprolol to a-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P < 0.001).3 The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. 4 The major urinary metabolite of metoprolol metabolism was H117-04, the endproduct of O-dealkylation. The distribution of the log1o metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P < 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. 5 These results indicate that both the a-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. 6 Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 7 In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in six extensive (EM) and six poor (PM) debrisoquin metabolizers. In EM, plasma AUCs for (S)-metoprolol were 35% higher than for (R)-metoprolol, whereas in PM, AUCs for (S)-metoprolol were lower than for (R)-metoprolol. AUCs for total metoprolol correlated with the ratio of (S)- to (R)-metoprolol AUC. The renal clearance of metoprolol was also stereoselective but to the same extent in both EM and PM. Findings suggest that the enzyme system responsible for polymorphic oxidation of the debrisoquin-type is 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 hr: EM = 5.3 +/- 5.6%; PM = 18.9 +/- 3.8%).

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