title: Polymorphic metabolism of flestolol and other ester containing compounds by a carboxylesterase in New Zealand white rabbit blood and cornea.
abstract: Flestolol, N(1,1-dimethyl-2-ureidocthyl)-2-hydroxy-3-(o-fluorobenzoyloxy++ +) propylamine, (F), is an ester containing an ultra short-acting beta blocker intended for the treatment of myocardial dysfunctions. In vitro incubation of F, procaine, chloroprocaine, and atropine with blood from different New Zealand White (NZW) rabbits resulted in a bimodal distribution (70% fast, 30% slow) of ester hydrolysis rates. Using F as a model substrate, bimodal hydrolysis rates were also observed in NZW rabbit cornea but not aqueous humor, iris-ciliary body complex and ocular tissues of pigmented rabbits. In addition, the bimodal distribution of esterase activity was not observed in blood from rats, dogs, and humans. Incubation of esters at various positions of the phenoxypropanolamine nucleus of beta blockers with NZW rabbit blood indicated structural specificity of the carboxylesterase in terms of unimodal or biomodal distribution of activity. These results strongly suggest that the carboxylesterase in NZW rabbit blood that hydrolyzes F and similar compounds is atropine esterase as described in the literature.
authors.affiliation: DuPont Merck Pharmaceutical Company, Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, Newark, DE 19714, USA.
authors.forename: H F
authors.initials: HF
authors.lastname: Stampfli
authors.forename: C Y
authors.initials: CY
authors.lastname: Quon
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000097:blood / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000201:enzymology*; D004285:Dogs; D004952:Esters / Q000378:metabolism; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010858:Pigmentation / Q000502:physiology; D011412:Propanolamines / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
chemical_list: D000319:Adrenergic beta-Antagonists; D004952:Esters; D005464:Fluorobenzenes; D011412:Propanolamines; D002265:Carboxylic Ester Hydrolases; C047847:flestolol