Dose-Dependent Inhibition of Platelet Cyclooxygenase-1 and Monocyte Cyclooxygenase-2 by Meloxicam in Healthy Subjects1

Abstract

We evaluated whether therapeutic blood levels of meloxicam are associated with selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 and 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, according to a randomized, double-blind, crossover design. Before dosing and 24 h after the seventh dose of each regimen, heparinized whole blood samples were incubated with lipopolysaccharide (10 μg/ml) for 24 h at 37°C, and prostaglandin E₂ was measured in plasma as an index of monocyte COX-2 activity. The production of thromboxane B₂in whole blood allowed to clot at 37°C for 60 min was assessed as an index of platelet COX-1 activity. The administration of placebo did not significantly affect plasma prostaglandin E₂ (21.3 ± 7.5 versus 19.1 ± 4 ng/ml, mean ± S.D.,n = 11) or serum thromboxane B₂(426 ± 167 versus 425 ± 150 ng/ml) levels. In contrast, the administration of 7.5 and 15 mg of meloxicam caused dose-dependent 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 the IC₅₀ value of COX-2 in vitro, this biochemical selectivity was inadequate to clearly separate the effects of meloxicam on the two isozymes after oral dosing as a function of the daily dose and interindividual variation in steady-state plasma levels.