Preparation and Evaluation of Amino Acid Conjugates of Celecoxib as Prodrugs to Improve the Pharmacokinetic and Therapeutic Properties of Celecoxib
- 주제(키워드) celecoxib , prodrug , bioavailability , PK linearity , extended absorption , carrageenan-induced rat paw edema model
- 주제(기타) Pharmacology & Pharmacy
- 설명문(일반) [Lee, Yonghyun; Kim, Jungyun; Kim, Wooseong; Yoon, In-Soo; Jung, Yunjin] Pusan Natl Univ, Coll Pharm, Busan 46241, South Korea; [Lee, Yonghyun] Ewha Womans Univ, Dept Pharm, Coll Pharm, Seoul 03760, South Korea; [Lee, Yonghyun] Ewha Womans Univ, Grad Sch Pharm, Seoul 03760, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 MDPI
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000175127
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/pharmaceutics12111043
- PubMed https://pubmed.ncbi.nlm.nih.gov/33143357
초록/요약
Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely N-glycyl-aspart-1yl celecoxib (N-GA1C), glutam-1-yl celecoxib (G1C), and aspart-1yl celecoxib (A1C), for the sustained release of celecoxib in the intestine with limited systemic absorption. The celecoxib derivatives were converted to celecoxib in the intestinal contents. The conversion rates were in order of N-GA1C > G1C > A1C. Oral administration of the celecoxib derivatives (oral celecoxib derivatives) sustained the plasma concentration of celecoxib for 24 h, improving the BA and linearity of the PK profile of celecoxib. The peak concentrations (C-max) of celecoxib after oral celecoxib derivatives were lower than that after oral celecoxib. In a carrageenan-induced rat paw edema model, oral N-GA1C exhibited greater anti-inflammatory activity for a longer duration compared with oral celecoxib. The order of efficacy of the celecoxib derivatives was N-GA1C > G1C > A1C. Taken together, the prodrug approach is a feasible strategy to improve the PK and therapeutic properties of celecoxib, and among the celecoxib derivatives, N-GA1C may be the most promising prodrug of celecoxib.
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