Abstract
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 (Cmax) 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.
Highlights
Celecoxib, a selective COX-2 inhibitor, is one of the most popular anti-inflammatory drugs for the treatment of chronic inflammatory diseases such as arthritis [1,2]
At the predetermined time points, 20 μL of the solution was transferred into an HPLC vial, and the concentrations of aspart-1yl celecoxib (A1C), glutam-1-yl celecoxib (G1C), or N-glycyl-aspart-1yl celecoxib (N-GA1C) were analyzed by HPLC
Preparation of Celecoxib Derivatives Coupled with Amino Acids
Summary
A selective COX-2 inhibitor, is one of the most popular anti-inflammatory drugs for the treatment of chronic inflammatory diseases such as arthritis [1,2]. A prodrug, pharmacologically inactive, per se, is created by appropriate chemical modification of a parent drug, and it is chemically and/or biologically converted to the active parent drug after achieving its purpose [7,8] This chemical approach has been widely utilized to improve the BA of hydrophobic drugs and/or the sustainability of drug action [7,8]. Hydrophilicity and the controlled release property of prodrugs are expected to improve the dissolution of the BCS class II drug and sustain the absorption of the parent drug while limiting the systemic absorption of the prodrug in the intestine. We examined if such improvement in PK properties translates into an improved therapeutic action of celecoxib against carrageenan-induced paw edema in rats
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