Effects of rofecoxib on lipid oxidation in plasma and aortas of rats

Abstract

-A selective cylooxygenase-2 (COX-2) inhibitor, rofecoxib, was withdrawn from the worldwide market due to an increased risk of cardiovascular (CV) events. A hypothesis has been proposed that rofecoxib promotes lipid oxidation, which increases the risk of CV events. However, this hypothesis was only predicated on in vitro experiments using isolated human low density lipoprotein and diluted human plasma. In the present study we investigated the effect of rofecoxib on the in vitro and in vivo production of thiorbarbituric acid reacting substance (TBARS) as an indicator of oxidation in plasma and aortas in rats. In vitro experiment, the TBARS production in plasma and aortic homogenate was not changed by the addition of rofecoxib at 2 μM, which concentration is around the maximum plasma concentration at clinical doses, or even at 200 μM. In addition, the production was not increased by rofecoxib in the presence of FeSO 4 as a typical oxidant. Meanwhile the TBARS production in the aorta of rats after 4-weeks administration of 10 mg/kg/day rofecoxib was comparable to that of the control rats. These results in-vitro and in-vivo experiments suggest that rofecoxib would have no or very weak effect on lipid oxidation in clinical usage, and it is thought that the increase of CV events already reported stemmed from causes other than oxidative stress.