Release characteristics of a short-chain fatty acid, n-butyric acid, from its beta-cyclodextrin ester conjugate in rat biological media

6(A)-O-(n-Butanoyl)-beta -cyclodextrin was prepared and its hydrolysis beha vior in aqueous solutions and in rat intestinal fluids was investigated. Fu rthermore, the enzymatic hydrolyses of the n-butyric acid-beta -cyclodextri n conjugate using alpha -amylase and esterase were studied to gain insight into the release behavior of n-butyric acid from the conjugate. The hydroly sis of the conjugate proceeded according to a first-order kinetics in aqueo us solution, and gave a V-shaped pH profile, indicating a specific acid-bas e-catalyzed hydrolysis at acidic and neutral-alkaline regions, respectively . The half-lives (t(1/2)) of the conjugate at pH 4.4, 6.8, and 7.4 at 37 de greesC were similar to 580, 43, and 6 days, respectively, indicating that t he conjugate is stable in aqueous solution. No appreciable release of n-but yric acid from the conjugate was observed in the stomach and small intestin al contents of rats, or in the small and large intestinal homogenates of ra ts. On the other hand, a fast disappearance of the conjugate and an appeara nce of n-butyric acid were observed in the cecal and colonic contents of ra ts. The t(1/2) values of the disappearance were similar to4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the a ppearance of n-butyric acid after 6 h was similar to 10% in the 15% cecal c ontents. Aspergillus oryzae alpha -amylase hydrolyzed the conjugate to smal l saccharide conjugates, such as the triose and maltose conjugates, but the re was no appreciable release of n-butyric acid. The conjugate was less sus ceptible to carboxylic esterase (from porcine live), thus releasing no appr eciable amounts of n-butyric acid. On the other hand, a fast release of n-b utyric acid was observed when the esterase was employed after amylase hydro lysis, suggesting that two types of enzymes, sugar-degrading and ester-hydr olyzing enzymes, are necessary for the release of n-butyric acid from the c onjugate in large intestinal contents. (C) 2000 Wiley-Liss Inc. and the Ame rican Pharmaceutical Association.