Beta 1-adrenoceptor subtype selective antagonism of esmolol and its major metabolite in vitro and in man. Investigations using tricresylphosphate as red blood cell carboxylesterase inhibitor.

Esmolol (CAS 103598-03-4, ASL-8052, Brevibloc) is an ultrashort acting beta-adrenoceptor antagonist which is rapidly hydrolyzed by a red blood cell esterase. In order to investigate the affinity profile of esmolol and its acid metabolite at beta-adrenoceptor subtypes in plasma and in whole blood in radioligand binding studies a potent esterase inhibitor was needed to prevent hydrolysis of esmolol and--in contrast to sodium fluoride--without influencing binding of the drugs at the receptor site. Tricresylphosphate was found to be a potent inhibitor of hydrolysis of esmolol which did not affect the parameters of radioligand binding. During an incubation time of 15 min at 25 degrees C in whole blood no significant metabolism of esmolol took place whereas without addition of inhibitor about 20% were inactivated. Thus, for the first time exact determinations of plasma concentrations of esmolol by ligand binding studies could be carried out. In vitro in radioligand binding studies esmolol had a 34 fold higher affinity for beta 1-adrenoceptors than for beta 2-adrenoceptors. Its acid metabolite had a very low and nonselective affinity for both adrenoceptor subtypes: Compared with esmolol it was 400fold less potent at beta 1-adrenoceptors. When plasma concentrations of esmolol and its metabolite after i.v. administration of esmolol to healthy volunteers (3000 micrograms/kg as a bolus and consecutively 500 micrograms/kg/min for 70 min) were determined in parallel by a beta 1-selective radioreceptor assay and an HPLC-method the following conclusions could be drawn from the direct correlation between the respective results: 1. (ABSTRACT TRUNCATED AT 250 WORDS)

Esmolol, an ultrashort-acting, selective beta 1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties.

The effects of esmolol at different rates of infusion (100, 250 and 500 micrograms.kg-1 BW.min-1) were compared with beta-adrenoceptor occupancy (beta 1 and beta 2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 micrograms.kg-1 BW.min-1 there was a maximal beta 1-receptor occupancy of 84.7% while beta 2-receptor occupancy was below the detection limit; confirming the beta 1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 micrograms.kg-1 BW.min-1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 micrograms.ml-1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 micrograms.kg-1 BW.min-1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)