Vol. 290, Issue 1, 276-280, July 1999

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

Maria R. Panara, Giulia Renda, Maria G. Sciulli, Giovanna Santini, Maria Di Giamberardino, Maria T. Rotondo, Stefania Tacconelli, Francesca Seta, Carlo Patrono and Paola Patrignani

Department of Medicine and Aging, Division of Pharmacology, University of Chieti "G. D'Annunzio" School of Medicine, Chieti, Italy

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 B₂ in 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.