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Vitamin C and 6-amino-vitamin C conjugates of diclofenac: synthesis and evaluation

International Journal of Pharmaceutics
Publication Date
DOI: 10.1016/j.ijpharm.2004.07.054
  • Diclofenac
  • Ascorbic Acid
  • Pro-Drug
  • Svct2
  • Synthesis
  • Stability
  • Biology


Abstract Diclofenac (Diclo), its ascorbic acid (AA) or 6-amino-AA (AA-NH 2) pro-drugs (AA-Diclo or AA-NH-Diclo) were prepared and evaluated on human retinal pigment epithelium (HRPE) cells to investigate their ability to interact with the vitamin C transporter SVCT2 and their cellular uptake. Furthermore, stabilities in physiological fluids of these compounds were investigated. For kinetic experiments, AA-Diclo was incubated in Tris–HCl buffer, human plasma or whole blood. The extracted samples were analysed by HPLC. AA-Diclo was hydrolysed following first order kinetics in buffer, plasma ( t 1/2 about 10 h) and whole blood ( t 1/2 about 3.5 h). Transport and inhibition assays were performed by adding [ 14C]AA and the above-mentioned unlabelled compounds to plated HRPE cells. Intracellular accumulation was measured incubating HRPE cells with increasing concentrations of unlabelled compounds, following by HPLC analysis. Diclo resulted as a non-competitive inhibitor of AA-transport, showing a Na +-dependent and ascorbate-independent uptake. AA-Diclo behaved as a competitive inhibitor, but it was not transported into cells, whereas its analogue AA-NH-Diclo showed a decreased inhibitory activity. Stability studies suggest AA-Diclo as a potential candidate to enhance the Diclo short half life in vivo. The discovery of a Na +-dependent transporter for Diclo on HRPE cells opens new perspectives for targeting diclofenac into the brain.

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