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 behavior in aqueous solutions and in rat intestinal fluids was investigated. Furthermore, the enzymatic hydrolyses of the n-butyric acid-beta-cyclodextrin conjugate using alpha-amylase and esterase were studied to gain insight into the release behavior of n-butyric acid from the conjugate. The hydrolysis of the conjugate proceeded according to a first-order kinetics in aqueous solution, and gave a V-shaped pH profile, indicating a specific acid-base-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 degrees C were approximately 580, 43, and 6 days, respectively, indicating that the conjugate is stable in aqueous solution. No appreciable release of n-butyric acid from the conjugate was observed in the stomach and small intestinal contents of rats, or in the small and large intestinal homogenates of rats. On the other hand, a fast disappearance of the conjugate and an appearance of n-butyric acid were observed in the cecal and colonic contents of rats. The t(1/2) values of the disappearance were approximately 4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the appearance of n-butyric acid after 6 h was approximately 10% in the 15% cecal contents. Aspergillus oryzae alpha-amylase hydrolyzed the conjugate to small saccharide conjugates, such as the triose and maltose conjugates, but there was no appreciable release of n-butyric acid. The conjugate was less susceptible to carboxylic esterase (from porcine live), thus releasing no appreciable amounts of n-butyric acid. On the other hand, a fast release of n-butyric acid was observed when the esterase was employed after amylase hydrolysis, suggesting that two types of enzymes, sugar-degrading and ester-hydrolyzing enzymes, are necessary for the release of n-butyric acid from the conjugate in large intestinal contents.
Hirayama
F
F
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Ogata
T
T
Yano
H
H
Arima
H
H
Udo
K
K
Takano
M
M
Uekama
K
K
D000818:Animals; D020148:Butyric Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D003470:Culture Media; D003505:Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics*; D004952:Esters / Q000737:chemistry / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000737:chemistry / Q000493:pharmacokinetics; D005503:Food Additives / Q000737:chemistry / Q000493:pharmacokinetics*; D006633:Histamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D047392:beta-Cyclodextrins
D003470:Culture Media; D003505:Cyclodextrins; D004952:Esters; D005227:Fatty Acids; D005503:Food Additives; D006633:Histamine Antagonists; D047392:beta-Cyclodextrins; D020148:Butyric Acid; C031215:betadex