Colon-specific delivery of celecoxib is a potential strategy to improve toxicological and pharmacological properties of the selective Cox-2 inhibitor: implication in treatment of familiar adenomatous polyposis.
In general, colon-specific delivery of a drug decreases systemic absorption and increases therapeutic concentration of the drug at the target site. N-succinylglutam-1 or 5-yl celecoxib (SG1C and SG5C) were prepared as a colon-specific prodrug of celecoxib, a selective Cox-2 inhibitor, and investigated whether the celecoxib derivatives could deliver celecoxib to the target site and improve cardiovascular toxicity and therapeutic effectiveness for the treatment of familiar adenomatous polyposis. SG1C and SA5C were cleaved to release celecoxib in the cecal contents while stable in small intestinal contents. The cecal release of celecoxib was much greater for SG1C than SG5C. SG1C administered orally was barely detected in the blood and urine. SG1C delivered much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level compared with oral administration of free celecoxib. Consistent with these pharmacokinetic results, SG1C supplied a greater concentration of celecoxib for the entire colonic tissue and did not change the serum level of 6-keto-PGF(1α) whose decrease is associated with the cardiovascular toxicity of celecoxib. Taken together, colon-specific delivery of celecoxib using a prodrug approach may be a useful strategy to improve toxicological and pharmacological properties of celecoxib.
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan, South Korea.
Yonghyun
Y
Lee
Hyunjeong
H
Kim
Wooseong
W
Kim
Jeong-Hyun
JH
Yoon
Seong Hoon
SH
Jeong
Yunjin
Y
Jung
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D002432:Cecum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000068579:Celecoxib; D060326:Chemistry Techniques, Synthetic; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D016503:Drug Delivery Systems; D004355:Drug Stability; D005971:Glutamates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D007408:Intestinal Absorption; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D014018:Tissue Distribution
D052246:Cyclooxygenase 2 Inhibitors; D005971:Glutamates; C573818:N-succinylaspart-1-yl celecoxib; C575808:N-succinylglutam-5-yl celecoxib; D011355:Prodrugs; D011720:Pyrazoles; D013449:Sulfonamides; D001224:Aspartic Acid; D015121:6-Ketoprostaglandin F1 alpha; D000068579:Celecoxib