N,N'-Bis(5-aminosalicyl)-L-cystine is a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis.
To evaluate N,N'-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) as a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis, the pharmacokinetics and therapeutic activity were investigated after oral administration of 5-ASA-Cys and amelioration of experimental colitis was compared after rectal administration of 5-aminosalicylic acid (5-ASA) and/or cysteine. In addition, the gluthathione (GSH) level in the inflamed colonic tissue was examined after administration of cysteine or 5-ASA-Cys. Oral administration of 5-ASA-Cys delivered much greater amount of 5-ASA to the large intestine and excreted lower amount of 5-ASA via urine than that of free 5-ASA. Oral administration of 5-ASA-Cys ameliorated experimental colitis of rats induced by TNBS, which was more effective than that of sulfasalazine. Although cysteine administered rectally was not significantly effective, intracolonic treatment with both 5-ASA and cysteine showed a synergic effect in alleviating the rat colitis. Furthermore, not only 5-ASA-Cys administered orally but also cysteine administered rectally increased the glutathione level in the inflamed colonic tissue. Taken together, these results suggest that 5-ASA-Cys is a potential colon specific 5-ASA prodrug with dual therapeutic effects on experimental colitis and cysteine modulation of the glutathione level may be relevant to the dual effects of the prodrug.
Kim
Heejung
H
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, South Korea.
Huh
Jeongsoon
J
Jeon
Hyunchu
H
Choi
Daekyu
D
Han
Jungoh
J
Kim
Youngmi
Y
Jung
Yunjin
Y
D000636:Aminosalicylic Acids / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003553:Cystine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
D000636:Aminosalicylic Acids; C528877:N,N'-bis(5-aminosalicyl)cystine; D011355:Prodrugs; D003553:Cystine