Dexamethasone 21-sulfate improves the therapeutic properties of dexamethasone against experimental rat colitis by specifically delivering the steroid to the large intestine.
OBJECTIVE
We investigated in vivo-colon targetability and therapeutic properties of DS against experimental rat colitis.


METHODS
The systemic absorption and colonic delivery of D after oral administration of DS was analyzed by examining the concentration of drugs in the GI tract, plasma, urine and feces. Therapeutic activity of DS was determined using a TNBS-induced rat colitis model. Adrenal suppression by DS administration was evaluated by monitoring the concentration of ACTH and corticosterone in the plasma.


RESULTS
DS administered orally was delivered efficiently to the large intestine resulting in D accumulation at the target site. In addition, DS was not detectable in the plasma and was detected very low in the urine after DS administration. The fecal and urinary recovery of D (after DS administration) was much greater and less than that after D administration, suggesting that DS should exhibit enhanced therapeutic activity and reduced systemic side effects. Consistent with this notion, DS was more effective than D in healing rat colitis. Moreover, oral administration of either D or DS reduced the plasma corticosterone and ACTH levels from the normal levels, which is significantly greater for D.


CONCLUSIONS
DS is a promising colon specific prodrug that improves therapeutic properties of D.
Kim
Inho
I
Laboratory of Biomedicinal/Medicinal Chemistry, College of Pharmacy, Pusan National University, Pusan, 609-735, Republic of Korea.
Kong
Hyesik
H
Lee
Younghyun
Y
Hong
Sungchae
S
Han
Jungoh
J
Jung
Sunhwa
S
Jung
Yunjin
Y
Kim
Young Mi
YM
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006854:Hydrocortisone / Q000097:blood; D007408:Intestinal Absorption; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014302:Trinitrobenzenesulfonic Acid
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D011355:Prodrugs; D013431:Sulfates; D003907:Dexamethasone; D014302:Trinitrobenzenesulfonic Acid; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone