Hydrolysis kinetics of 1,3-benzoxazine-2,4-dione (a potential salicylamide prodrug) and various N-substituted derivatives.
The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.
Kahns
A H
AH
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
Bundgaard
H
H
D000818:Animals; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D010078:Oxazines / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D012457:Salicylamides / Q000493:pharmacokinetics*
D010078:Oxazines; D011355:Prodrugs; D012457:Salicylamides; C065957:carsalam; C031060:salicylamide