Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects

We evaluated whether therapeutic blood levels of meloxicam are associated w ith selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 a nd platelet COX-1 were obtained in vitro after the incubation of meloxicam with whole blood samples. Moreover, 11 healthy volunteers received placebo or 7.5 or 15 mg/day meloxicam, each treatment for 7 consecutive days, accor ding to a randomized, double-blind, crossover design. Before dosing and 24 h after the seventh dose of each regimen, heparinized whole blood samples w ere incubated with lipopolysaccharide (10 mu g/ml) for 24 h at 37 degrees C , and prostaglandin E-2 was measured in plasma as an index of monocyte COX- 2 activity. The production of thromboxane B-2 in whole blood allowed to clo t at 37 degrees C for 60 min was assessed as an index of platelet COX-1 act ivity. The administration of placebo did not significantly affect plasma pr ostaglandin E-2 (21.3 +/- 7.5 versus 19.1 +/- 4 ng/ml, mean +/- S.D., n = 1 1) or serum thromboxane B-2 (426 +/- 167 versus 425 +/- 150 ng/ml) levels. In contrast, the administration of 7.5 and 15 mg of meloxicam caused dose-d ependent reductions in monocyte COX-2 activity by 51% and 70%, respectively , and in platelet COX-1 activity by 25% and 35%, respectively. Although the IC50 value of meloxicam for inhibition of COX-1 was 10-fold higher than th e IC50 value of COX-2 in vitro, this biochemical selectivity was inadequate to clearly separate the effects of meloxicam on the two isozymes after ora l dosing as a function of the daily dose and interindividual variation in s teady-state plasma levels.