Synthesis and in vitro properties of dexamethasone 21-sulfate sodium as a colon-specific prodrug of dexamethasone.
We synthesized dexamethasone 21-sulfate sodium (DS) as a colon-specific prodrug of dexamethasone and investigated its properties. Introduction of a sulfate group to dexamethasone lowered the apparent partition coefficient from 52.5 to 0.27 in 1-octanol/pH 6.8 phosphate buffer at 37 degrees C. DS was stable on incubation with buffer solutions of varied pH or with the upper intestinal contents of rats at 37 degrees C for 24 h. On incubation with the cecal contents, DS was hydrolyzed by producing dexamethasone over 80% of the dose at 10 h. When DS was incubated with the cecal contents collected from trinitrobenzenesulfonic acid (TNBS)-induced colitic rats, the degree of prodrug hydrolysis and production of dexamethasone amounted to 70% of healthy rats. In comparison with prednisolone, hydrocortisone, and cortisone, dexamethasone was stable against bioinactivation by the cecal contents, a desirable property for the development of a colon-specific prodrug. These results demonstrated that DS might be delivered specifically to the colon as an intact form to produce dexamethasone in high yield, suggesting DS as a potential colon-specific prodrug of dexamethasone.
Kim
In Ho
IH
College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan, Korea.
Kong
Hye Sik
HS
Choi
Bo Im
BI
Kim
Young Soo
YS
Kim
Hee Jung
HJ
Yang
Young Wook
YW
Jung
Yun Jin
YJ
Kim
Young Mi
YM
D000818:Animals; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D011355:Prodrugs; C016356:dexamethasone sulfate ester; D003907:Dexamethasone