5-Fluorouracil acetic acid/beta-cyclodextrin conjugates: drug release behavior in enzymatic and rat cecal media.

5-Fluorouracil-1-acetic acid (5-FUA) was prepared and covalently conjugated to beta-cyclodextrin (beta-CyD) through ester or amide linkage, and the drug release behavior of the conjugates in enzymatic solutions and rat cecal contents were investigated. The 5-FUA/beta-CyD ester conjugate was slowly hydrolyzed to 5-FUA in aqueous solutions (half lives (t(1/2))=38 and 17h at pH 6.8 and 7.4, respectively, at 37 degrees C), whereas the amide conjugate was hardly hydrolyzed at these physiological conditions, but hydrolyzed only in strong alkaline solutions (>0.1M NaOH) at 60 degrees C. Both ester and amide conjugates were degraded in solutions of a sugar-degrading enzyme, alpha-amylase, to 5-FUA/maltose and triose conjugates, but the release of 5-FUA was only slight in alpha-amylase solutions. In solutions of an ester-hydrolyzing enzyme, carboxylic esterase, the ester conjugate was hydrolyzed to 5-FUA at the same rate as that in the absence of the enzyme, whereas the amide conjugate was not hydrolyzed by the enzyme. On the other hand, 5-FUA was rapidly released when the ester conjugate was firstly hydrolyzed by alpha-amylase, followed secondly by carboxylic esterase. The results indicated that the ester conjugate was hydrolyzed to 5-FUA in a consecutive manner, i.e. it was firstly hydrolyzed to the small saccharide conjugates, such as the maltose conjugate, by alpha-amylase, and the resulting small saccharide conjugates having less steric hindrance was susceptible to the action of carboxylic esterase, giving 5-FUA. The in vitro release behavior of the ester conjugate was clearly reflected in the hydrolysis in rat cecal contents and in the in vivo release after oral administration to rats. Copyright (c) 2009 Elsevier B.V. All rights reserved.