A nonsteady-state agonist antagonist interaction model using plasma potassium concentrations to quantify the beta-2 selectivity of beta blockers

We studied the competitive interaction of terbutaline and two beta blockers, metoprolol and oxprenolol, with different cardioselectivity for the beta-2 adrenoceptor. Using pharmacokinetic-dynamic modeling in nonsteady-state conditions, of the antagonism by the beta blockers of the terbutaline-induced hypokalemia, the beta blocker beta-2 selectivity was quantitated in the terms of IC50 values representing plasma concentrations resulting in half-receptor occupancy. Six healthy subjects were given an 0.5-mg s.c. dose of terbutaline on three occasions: 1) 1 hr after p.o. administration of a placebo; 2) 1 hr after 150 mg of metoprolol p.o.; and 3) 1 hr after 80 mg of oxprenolol p.o. During 7 hr after terbutaline administration drug concentrations and effects were monitored. Oxprenolol decreased both terbutaline volume of distribution (-69%) and clearance (-63%) and increased its area under plasma concentrations vs. time curve (+157%). Such effects of metoprolol on terbutaline pharmacokinetics were not observed. The dynamic model offered a good description of the observed effects. The apparent IC50 values varied between 42 and 68 ng/ml (mean, 54 ng/ml) for metoprolol and between 3.6 and 4.7 ng/ml (mean, 4.1 ng/ml) for oxprenolol. In view of these results, and comparing them with apparent beta-1 IC50 values as reported in the literature, metoprolol can be considered a relatively beta-1 selective agent. Pharmacokinetic-dynamic modeling of the interaction of beta-2 sympathicomimetics and beta blocking agents after single dosing, seems to be a suitable method for the determination of the relative beta-2 selectivity of the antagonist