The Biochemical Selectivity of Novel COX-2 Inhibitors in Whole Blood Assays of COX-isozyme Activity

Summary

We have evaluated the biochemical selectivity of novel cyclo-oxygenase (COX)-2 inhibitors, etoricoxib, valdecoxib, DFU and DFP, vs rofecoxib and celecoxib, using the human whole blood assays of COX-isozyme activity, in vitro. Compounds were incubated with human whole blood samples, allowed to clot for 1 h at 37°C, or stimulated with lipopolysaccharide (10|ig/ml) for 24 h at 37°C. Serum thromboxane (TX) B2 and plasma prostaglandin (PG) E2 levels were measured by specific radioimmunoassays as indices of platelet COX-1 and monocyte COX-2 activity, respectively. Valdecoxib, etoricoxib, DFU

and DFP inhibited platelet COX-1 and monocyte COX-2 with the following COX-1/COX-2 IC50 ratios: 61.5, 344, 660 and 1918, respectively. The reference compounds, celecoxib and rofecoxib had corresponding values of 29.6 and 272. In conclusion, a second wave of COX-2 inhibitors with higher biochemical selectivity than the existing coxibs has been developed. Whether their administration will be associated with improved clinical efficacy and/or safety visà-vis celecoxib and rofecoxib remains to be established.

Key Words::

• Cyclo-oxygenase-1
• Cyclo-oxygenase-2
• Etoricoxib
• Human whole blood
• Rofecoxib
• Valdecoxib