Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.21 (beta-glucosidase)
 3,280 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained beta-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, less than 1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.
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PMID:Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig. 187 Oct 38

In the liver of suckling rats, the synthesis of hepatic tyrosine aminotransferase, serine dehydratase, and phosphofructokinase 2 as well as of renal beta-glucosidase is controlled by the circulating concentrations of adrenal and pancreatic hormones. Glucagon is capable of stimulating enzyme synthesis only in the presence of a steroid hormone. Dexamethasone and estradiol have been found to exert a permissive function on the inducibility of the studied enzymes by glucagon. Between the hormones of the adrenal medulla and glucagon antagonistic effects in enzyme induction were observed. Obviously, this antagonism is mediated by the alpha 1-adrenergic signal transferring system. A characteristic age dependence of enzyme induction by dexamethasone has been established. This might be correlated to alterations in the degree of methylation of the respective promoters. The methylation inhibitor 5-azacytidine influences significantly the enzyme induction by glucocorticoid hormones.
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PMID:Interaction of adrenal and pancreatic hormones in the control of hepatic enzymes during development. 289 Feb 81

Dexamethasone-beta-D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445-454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone-beta-D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl-beta-D-glucoside and -beta-D-glucuronide) and to evaluate the prodrug dexamethasone-beta-D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (beta-D-glucosidase and beta-D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of beta-D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal beta-D-glucuronidase activity in the large intestine; however, beta-D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal beta-D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of beta-D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone-beta-D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of beta-D-glucuronidase activity in the small intestine compared with that in the laboratory rat.
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PMID:In vitro evaluation of dexamethasone-beta-D-glucuronide for colon-specific drug delivery. 829 Apr 67