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Metoprolol metabolism and debrisoquine oxidation polymorphism--population and family studies.

The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117-04, the end-product of O-dealkylation. The distribution of the log10 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 less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. These results indicate that both the alpha-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. 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.