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Abstract #15773 Published in IGR 2-3
In vitro and ex vivo hydrolysis rates of ethacrynate esters and their relationship to intraocular pressure in the rabbit eye
Deshpande G; Schoenwald RD; Barfknecht CF; Duffel MWJournal of Ocular Pharmacology and Therapeutics 2000; 16: 539-556
Esters of ethacrynic acid and partial structural analogues were synthesized and evaluated for topical antiglaucoma activity in rabbits. Maximum activity was shown by analogues 2 and 6 (34% and 30% reduction in intraocular pressure recovery rate, respectively). Among the esters, only the ethyl ester (2) was found to be active; the methyl and n-propyl esters (1 and 3) were inactive. Analogues 1-3 were subjected to an estimation of physicochemical properties and chemical stability. However, no correlation was found to exist between the biological activity/inactivity and the physicochemical properties of the analogues. The analogues were evaluated for ex vivo hydrolysis using rabbit aqueous humor (AH), corneal (C) homogenate and iris-ciliary body (ICB) homogenate. For all tissues, the rate of enzymatic hydrolysis increased significantly with an increasing ester chain length. The ICB-mediated hydrolysis was the fastest among the three tissues for all the analogues. The relationship between the rate constants for the tissue-mediated hydrolyses were: analogue 1, ICB>C>AH; analogue 2, ICB>C=AH and analogue 3, ICB>AH>C. Apparent Michaelis-Menten kinetic parameters were determined for the three analogues using corneal homogenate. Analogue 2 showed the highest v0 for all substrate concentrations studied. The conventional Michaelis-Menten equation did not fit the data as well as a sigmoidal model. Both fits of the data showed the fastest enzyme-mediated hydrolysis for analogue 2. The parameters of the sigmoidal fit of the data correlated with the activity/inactivity of the analogues. The data indicate that the major factors responsible for the observed activity/inactivity are the differences in the corneal enzymatic hydrolysis of the esters in conjunction with the rapid dynamics of ocular prodrug absorption.
Dr. G. Deshpande, Division of Pharmaceutics, College of Pharmacy, The University of Iowa, Iowa City 52242, Iowa, USA
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
