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)