title: 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.
abstract: 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)
authors.affiliation: Zentrum der Pharmakologie, Johann Wolfgang Goethe-Universität, Frankfurt/Main, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Jahn
authors.forename: B
authors.initials: B
authors.lastname: Eckrich
authors.forename: B
authors.initials: B
authors.lastname: Schneidrowski
authors.forename: C
authors.initials: C
authors.lastname: Volz-Zang
authors.forename: B
authors.initials: B
authors.lastname: Schulte
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: D
authors.initials: D
authors.lastname: Palm
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D014317:Tritolyl Phosphates / Q000494:pharmacology*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D014317:Tritolyl Phosphates; D002265:Carboxylic Ester Hydrolases; C036604:esmolol; C025541:tri-o-cresyl phosphate