Plasma levels and beta-blocking effect of alpha-hydroxymetoprolol--metabolite of metoprolol--in the dog.

The plasma levels and the beta-blocking effect of metoprolol and its active metabolite alpha-hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the beta-blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of beta-blockade. Because of differences in the volume of distribution, 2.0 liters/kg for alpha-OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of alpha-OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. alpha-OH-Metoprolol was more slowly eliminated (t1/2 approximately 7.0 hr, total body clearance approximately 3.5 ml-kg-1-min-1) than metoprolol (t 1/2 approximately 2.0 hr, total body clearance approximately 20.0 ml-kg-1-min-1). Approximately 5% of an i.v. dose of metoprolol was metabolized to alpha-OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.