Polymorphic metabolism of metoprolol: clinical studies.

After a single 200 mg oral dose of metoprolol tartrate the mean metoprolol AUC was found to be six-fold higher in poor metabolizers (PMs) of debrisoquine than in extensive metabolizers (EMs). This was associated with impaired metabolic clearance via alpha-hydroxylation and O-dealkylation. A population study (n = 143) has shown a bimodal distribution in the ratio of metoprolol: alpha-hydroxymetoprolol recovered in urine which was correlated highly with the debrisoquine metabolic ratio. Nine per cent of the population were PMs. Plasma metoprolol concentrations three hours after a 100 mg oral dose of metoprolol were greater than 200 ng/ml in PMs but were lower than this in most EMs. This dose of metoprolol given once daily provided a clinically significant reduction (16%) in exercise heart rate in PMs after 24 hours. EMs require conventional doses (100 mg b.d.) to achieve the same degree of beta-blockade. Preliminary data from family studies support the view that the defect in metoprolol oxidation is inherited. In 12 hypertensive patients who were EMs we compared the beta-blocking activity and antihypertensive effect of chronic treatment with metoprolol 200 mg once daily (conventional and long-acting formulations), with those of atenolol 100 mg once daily and placebo. The effects of all active preparations were similar at 3.5 hours but atenolol was superior to all metoprolol formulations at 24 hours after dosing. It is concluded that for the majority of patients metoprolol should be prescribed twice daily when using currently available dosage forms. Relationships between oxidation phenotype and side-effects should be examined.