Synthesis of an enzyme-dependent prodrug and evaluation of its potential for colon targeting.
OBJECTIVE
To synthesize dexamethasone-succinate-dextran (DSD) conjugate and to evaluate the potentiality of DSD for the treatment of inflammatory bowel diseases.


METHODS
Dexamethasone was attached to dextran (average molecular weight=70,400 Dalton) using succinate anhydride in an anhydrous environment catalyzed by 4-dimethylaminopyridine and 1, 1'-carbonyldiimidazole. The chemical structure of DSD was identified by UV, IR and NMR, and the in vivo drug release behavior of this prodrug was investigated after oral administration of DSD suspension.


RESULTS
The DSD conjugate was obtained in two steps and the content of dexamethasone in DSD was 11.28 %. The dextran prodrug was stable in rat stomach and small intestine and negligibly absorbed from these tracts. Four to nine hours after the oral administration, most of the prodrug (>95 %) had moved to the cecum and colon, and was easily hydrolyzed by an endodextranase. Recover of dexamethasone from colon and cecum after administration of DSD conjugate was 6-12 folds higher than the recovery after administration of unmodified dexamethasone (t=2.74, P<0.05). The preferential release of free dexamethasone in cecum and colon over that in the small intestine was statistically significant (t=2.27, P<0.05).


CONCLUSIONS
The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the colon.
Pang
Yi-Nuo
YN
West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan Province, China.
Zhang
Yan
Y
Zhang
Zhi-Rong
ZR
D000818:Animals; D002152:Calorimetry, Differential Scanning; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D003911:Dextrans / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005938:Glucocorticoids / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000737:chemistry / Q000493:pharmacokinetics
D003911:Dextrans; D005938:Glucocorticoids; D011355:Prodrugs; D003907:Dexamethasone; D019802:Succinic Acid