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Celecoxib coupled to dextran via a glutamic acid linker yields a polymeric prodrug suitable for colonic delivery.

Lee Y, Kim J, Kim W, Nam J, Jeong S, Lee S, Yoo JW, Kim MS, Jung Y - Drug Des Devel Ther (2015)

Bottom Line: Generally, colon-specific delivery of a drug both increases the therapeutic availability in the large intestine and decreases the systemic absorption of the drug, most likely resulting in enhanced therapeutic effects against colonic diseases such as colitis and reduced systemic side effects.G1CD prevented the systemic absorption of celecoxib and did not decrease the serum level of 6-ketoprostaglandin F1α, an inverse indicator of cardiovascular toxicity of celecoxib.Collectively, G1CD may be a polymeric colon-specific celecoxib prodrug with therapeutic and toxicological advantages.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea ; Bio-Nanomedicine Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

ABSTRACT
Celecoxib, a selective cyclooxygenase-2 inhibitor, is potentially useful for the treatment of colonic diseases such as colorectal cancer and colitis. However, the cardiovascular toxicity of celecoxib limits its routine use in the clinic. Generally, colon-specific delivery of a drug both increases the therapeutic availability in the large intestine and decreases the systemic absorption of the drug, most likely resulting in enhanced therapeutic effects against colonic diseases such as colitis and reduced systemic side effects. To develop a colon-specific prodrug of celecoxib that could reduce its cardiovascular toxicity and improve its therapeutic activity, dextran-glutamic acid-celecoxib conjugate (glutam-1-yl celecoxib-dextran ester [G1CD]) was prepared and evaluated. While stable in pH 1.2 and 6.8 buffer solutions and small-intestinal contents, G1CD efficiently released celecoxib in cecal contents. Oral administration of G1CD to rats delivered a larger amount of celecoxib to the large intestine than free celecoxib. G1CD prevented the systemic absorption of celecoxib and did not decrease the serum level of 6-ketoprostaglandin F1α, an inverse indicator of cardiovascular toxicity of celecoxib. Collectively, G1CD may be a polymeric colon-specific celecoxib prodrug with therapeutic and toxicological advantages.

No MeSH data available.


Related in: MedlinePlus

Glutam-1-yl celecoxib-dextran ester (G1CD) does not affect the serum level of 6-ketoprostaglandin F1α (6-keto-PGF1α).Notes: (A) Celecoxib in the blood was analyzed by HPLC at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent mean ± SEM (n=5). (B) 6-keto-PGF1α in the blood was analyzed using an ELISA kit at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent the mean ± SEM (n=5). *P<0.05 vs control; **P>0.05 vs control; #P<0.05 vs celecoxib; ##P>0.05 vs celecoxib at each time point.Abbreviations: HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay.
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f4-dddt-9-4105: Glutam-1-yl celecoxib-dextran ester (G1CD) does not affect the serum level of 6-ketoprostaglandin F1α (6-keto-PGF1α).Notes: (A) Celecoxib in the blood was analyzed by HPLC at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent mean ± SEM (n=5). (B) 6-keto-PGF1α in the blood was analyzed using an ELISA kit at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent the mean ± SEM (n=5). *P<0.05 vs control; **P>0.05 vs control; #P<0.05 vs celecoxib; ##P>0.05 vs celecoxib at each time point.Abbreviations: HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay.

Mentions: Long-term use of celecoxib for the prevention of CRC or the treatment of colitis may cause cardiovascular toxicity, which is correlated with the concentration of celecoxib in blood.11 To examine whether G1CD could reduce the blood concentration of celecoxib, celecoxib or G1CD was administered orally to rats and the plasma concentrations of celecoxib were compared. As shown in Figure 4A, while the plasma concentration of celecoxib reached 2.8 μM at 2 hours after oral administration of celecoxib, celecoxib was not detectable in the plasma for 24 hours after oral administration of G1CD, indicating that G1CD limited the systemic absorption of celecoxib.


Celecoxib coupled to dextran via a glutamic acid linker yields a polymeric prodrug suitable for colonic delivery.

Lee Y, Kim J, Kim W, Nam J, Jeong S, Lee S, Yoo JW, Kim MS, Jung Y - Drug Des Devel Ther (2015)

Glutam-1-yl celecoxib-dextran ester (G1CD) does not affect the serum level of 6-ketoprostaglandin F1α (6-keto-PGF1α).Notes: (A) Celecoxib in the blood was analyzed by HPLC at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent mean ± SEM (n=5). (B) 6-keto-PGF1α in the blood was analyzed using an ELISA kit at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent the mean ± SEM (n=5). *P<0.05 vs control; **P>0.05 vs control; #P<0.05 vs celecoxib; ##P>0.05 vs celecoxib at each time point.Abbreviations: HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4524528&req=5

f4-dddt-9-4105: Glutam-1-yl celecoxib-dextran ester (G1CD) does not affect the serum level of 6-ketoprostaglandin F1α (6-keto-PGF1α).Notes: (A) Celecoxib in the blood was analyzed by HPLC at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent mean ± SEM (n=5). (B) 6-keto-PGF1α in the blood was analyzed using an ELISA kit at appropriate time intervals after oral administration of G1CD or celecoxib. The data represent the mean ± SEM (n=5). *P<0.05 vs control; **P>0.05 vs control; #P<0.05 vs celecoxib; ##P>0.05 vs celecoxib at each time point.Abbreviations: HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay.
Mentions: Long-term use of celecoxib for the prevention of CRC or the treatment of colitis may cause cardiovascular toxicity, which is correlated with the concentration of celecoxib in blood.11 To examine whether G1CD could reduce the blood concentration of celecoxib, celecoxib or G1CD was administered orally to rats and the plasma concentrations of celecoxib were compared. As shown in Figure 4A, while the plasma concentration of celecoxib reached 2.8 μM at 2 hours after oral administration of celecoxib, celecoxib was not detectable in the plasma for 24 hours after oral administration of G1CD, indicating that G1CD limited the systemic absorption of celecoxib.

Bottom Line: Generally, colon-specific delivery of a drug both increases the therapeutic availability in the large intestine and decreases the systemic absorption of the drug, most likely resulting in enhanced therapeutic effects against colonic diseases such as colitis and reduced systemic side effects.G1CD prevented the systemic absorption of celecoxib and did not decrease the serum level of 6-ketoprostaglandin F1α, an inverse indicator of cardiovascular toxicity of celecoxib.Collectively, G1CD may be a polymeric colon-specific celecoxib prodrug with therapeutic and toxicological advantages.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea ; Bio-Nanomedicine Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

ABSTRACT
Celecoxib, a selective cyclooxygenase-2 inhibitor, is potentially useful for the treatment of colonic diseases such as colorectal cancer and colitis. However, the cardiovascular toxicity of celecoxib limits its routine use in the clinic. Generally, colon-specific delivery of a drug both increases the therapeutic availability in the large intestine and decreases the systemic absorption of the drug, most likely resulting in enhanced therapeutic effects against colonic diseases such as colitis and reduced systemic side effects. To develop a colon-specific prodrug of celecoxib that could reduce its cardiovascular toxicity and improve its therapeutic activity, dextran-glutamic acid-celecoxib conjugate (glutam-1-yl celecoxib-dextran ester [G1CD]) was prepared and evaluated. While stable in pH 1.2 and 6.8 buffer solutions and small-intestinal contents, G1CD efficiently released celecoxib in cecal contents. Oral administration of G1CD to rats delivered a larger amount of celecoxib to the large intestine than free celecoxib. G1CD prevented the systemic absorption of celecoxib and did not decrease the serum level of 6-ketoprostaglandin F1α, an inverse indicator of cardiovascular toxicity of celecoxib. Collectively, G1CD may be a polymeric colon-specific celecoxib prodrug with therapeutic and toxicological advantages.

No MeSH data available.


Related in: MedlinePlus