ISSN:
1573-904X
Keywords:
nucleoside analogues
;
topical sustained release
;
enzymatic degradation
;
hydrolysis
;
chemical stability
;
adamantoate ester
;
DHPG
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract We report the chemical and enzymatic hydrolysis of two hydrophobic prodrugs of ganciclovir (3 = dipropionate ester; 4 = diadamantoate ester). Both prodrugs undergo hydrolysis showing a pH dependence of kobs = kH+ aH+ + ko + kHO-aHO− and a pH of maximum stability near pH 5. Only 4 exhibited a shelf life (t90) greater than 2 years. Compound 4 reacts significantly slower than ganciclovir in acidic media, even though the adamantyl esters provide additional reaction sites (which would be expected to increase the rate of degradation) that are distally removed from the guanine ring system, offering negligible steric or electronic substituent effects. Both 3 and 4 hydrolyzed in tissue homogenate, where kobs followed liver 〉 intestine ≫ skin. Based on these findings of chemical stability, lipophilicity, and acceptable rate of enzymatic cleavage by skin es-terases, 4 meets several of the criteria required for the topical sustained delivery of ganciclovir.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1015809408908
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