Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics. Many therapeutically useful drugs are metabolized by these proteins which impacts upon the efficiency of drug treatment. In some instances, CEs convert inactive prodrugs to active metabolites, a process that is essential for biological activity. Such compounds include the anticancer agents CPT-11 (3) and capecitabine (4), the antibiotics Ceftin (9) and Vantin, as well as the illicit street drug heroin (6). However, more commonly, CEs hydrolyze many esterified drugs to inactive products that are then excreted. Agents such as flestolol (11), meperidine (5), lidocaine (8) and cocaine (7), are all hydrolyzed and inactivated by these enzymes. Therefore the efficacy of esterified drugs will be dependent upon the distribution and catalytic activity of different CEs. In this review, we examine the structural aspects of CEs and their roles in drug detoxification and propose that modulation of CE activity may allow for improvements in, and potentiation of, drug efficacy.

01 Apr 1995·Research communications in molecular pathology and pharmacology

Polymorphic metabolism of flestolol and other ester containing compounds by a carboxylesterase in New Zealand white rabbit blood and cornea.

Article

Author: Quon, C Y ; Stampfli, H F

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.

01 Sep 1993·Research communications in chemical pathology and pharmacology

Biochemical characterization of flestolol esterase.

Article

Author: Stampfli, H F ; Quon, C Y

The blood esterase that mediates the metabolism of flestolol, an ultra short-acting beta blocker, was characterized. Esterase activity occurred in plasma of human, dog, rat, and guinea pig and not in erythrocytes of the same species. The esterase activity was greatest in humans and guinea pigs followed by dogs and rats. Purified human serum cholinesterase was very active against flestolol while human serum albumin was slightly active. Human and bovine erythrocyte membrane acetylcholinesterases, electric eel acetylcholinesterase, human hemoglobin, dog, rat, chicken, and bovine serum albumin were all inactive. Esterase activity with flestolol was inhibited in human, dog, and rat blood by echothiophate, eserine, and sodium fluoride. Guinea pig blood esterase activity was inhibited by echothiophate and sodium fluoride, but not by eserine. Metabolic interaction studies indicated that succinylcholine, procaine, and chloroprocaine interfere with the metabolism of flestolol in human blood. Succinylcholine prolonged the in vitro half-life of flestolol in dog blood, but acetylcholine, procaine, and chloroprocaine had no effect. Flestolol did not affect the metabolism of procaine or chloroprocaine in human and dog blood. The metabolism rate of flestolol decreased in individuals with atypical, fluoride-resistant and silent forms of serum cholinesterase.

100 Deals associated with Flestolol Sulfate

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KEGG	Wiki	ATC	Drug Bank
D04190	Flestolol Sulfate	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Phase 1	DE	-	-
Arrhythmias, Cardiac	Phase 1	-	Bristol Myers Squibb Co.	-
Myocardial Ischemia	Phase 1	US	Bristol Myers Squibb Co.	-
Heart Failure	Preclinical	US	American Hospital Supply Corp.	01 May 2002

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