Macromolecular drug conjugates II: chemical and enzymatic hydrolysis kinetics of the secondary 5-fluorouracil-1-acetic acid/β-cyclodextrin conjugate

The chemical and enzymatic hydrolysis of the secondary 5-fluorouracil-1-acetic acid/beta-cyclodextrin conjugate were evaluated for potential application as a colon-targeted prodrug. In aqueous buffer solutions at a pH of 1-10, the pH-rate profile for hydrolysis of the conjugate was interpreted in terms of spontaneous or water-catalyzed, and specific base-catalyzed reactions. In the solutions of alpha-amylase, the conjugate was degraded to 5-fluorouracil-1-acetic acid/small saccharide conjugates. In the solutions of carboxyl esterase, the conjugate was gradually hydrolyzed to 5-fluorouracil-1-acetic acid at the similar rate as that in the absence of the carboxyl esterase. 5-Fluorouracil-1-acetic acid was rapidly released when the conjugate was hydrolyzed firstly by alpha-amylase and secondly by carboxyl esterase. On the other hand, the rate of hydrolysis of the conjugate was accelerated significantly by the colonic fluids of rats. It is important to note that the secondary conjugate released the parent drugs more slowly than the primary one.