TY - JOUR
T1 - N-succinylaspart-1-yl celecoxib is a potential colon-specific prodrug of celecoxib with improved therapeutic properties
AU - Lee, Yonghyun
AU - Kim, Jeongyun
AU - Kim, Hyunjeong
AU - Kang, Sookjin
AU - Yoon, Jeong Hyun
AU - Kim, Dae Duk
AU - Kim, Young Mi
AU - Jung, Yunjin
N1 - Funding Information:
This work was supported by the Korea Research Foundation grant (number 521-2008-1-E00193) and the National Research Foundation of Korea grant (number 2009-0083533) funded by the Korea government (Ministry of Education, Science And Technology).
PY - 2012/5
Y1 - 2012/5
N2 - To develop a colon-specific prodrug of celecoxib, a cyclooxygenase-2 selective inhibitor, which could improve cardiovascular toxicity and therapeutic effectiveness for chemoprevention of colorectal cancer, aspart-1-yl celecoxib (A1C) or aspart-4-yl celecoxib (A4C), succinyl celecoxib (SC), and N-succinylaspart-1-yl celecoxib (SA1C) or N-succinylaspart-4-yl celecoxib (SA4C) were prepared and evaluated as a prodrug with such beneficial properties. On incubation with the small intestinal contents while SC, SA1C, and SA4C were stable, A1C and A4C were degraded to liberate celecoxib. In the cecal contents, the other conjugates except for SC and SA4C were cleaved to release celecoxib. These results suggest the colon-specific delivery and activation of SA1C. On oral administration of SA1C or celecoxib, no SA1C was detected in the blood and urine, indicating the limited absorption of SA1C. SA1C delivered a much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level, which is consistent with no change of the serum level of 6-ketoprostaglandin F1α whose decrease is associated with the cardiovascular toxicity of celecoxib. Moreover, SA1C administered orally supplied a greater concentration of celecoxib for the whole colonic tissue. Taken together, SA1C may be a colon-specific prodrug of celecoxib with improved therapeutic properties.
AB - To develop a colon-specific prodrug of celecoxib, a cyclooxygenase-2 selective inhibitor, which could improve cardiovascular toxicity and therapeutic effectiveness for chemoprevention of colorectal cancer, aspart-1-yl celecoxib (A1C) or aspart-4-yl celecoxib (A4C), succinyl celecoxib (SC), and N-succinylaspart-1-yl celecoxib (SA1C) or N-succinylaspart-4-yl celecoxib (SA4C) were prepared and evaluated as a prodrug with such beneficial properties. On incubation with the small intestinal contents while SC, SA1C, and SA4C were stable, A1C and A4C were degraded to liberate celecoxib. In the cecal contents, the other conjugates except for SC and SA4C were cleaved to release celecoxib. These results suggest the colon-specific delivery and activation of SA1C. On oral administration of SA1C or celecoxib, no SA1C was detected in the blood and urine, indicating the limited absorption of SA1C. SA1C delivered a much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level, which is consistent with no change of the serum level of 6-ketoprostaglandin F1α whose decrease is associated with the cardiovascular toxicity of celecoxib. Moreover, SA1C administered orally supplied a greater concentration of celecoxib for the whole colonic tissue. Taken together, SA1C may be a colon-specific prodrug of celecoxib with improved therapeutic properties.
KW - Cardiovascular toxicity
KW - Celecoxib
KW - Chemoprevention
KW - Colonic drug delivery
KW - Controlled release/delivery
KW - Familial adenomatous polyposis
KW - Oral drug delivery
KW - Prodrugs
KW - Site-specific delivery
UR - http://www.scopus.com/inward/record.url?scp=84861827022&partnerID=8YFLogxK
U2 - 10.1002/jps.23082
DO - 10.1002/jps.23082
M3 - Article
C2 - 22334096
AN - SCOPUS:84861827022
SN - 0022-3549
VL - 101
SP - 1831
EP - 1842
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 5
ER -