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COVALENT BINDING OF RADIOACTIVITY FROM [¹⁴C]ROFECOXIB, BUT NOT [¹⁴C]CELECOXIB OR [¹⁴C]CS-706, TO THE ARTERIAL ELASTIN OF RATS

Drug Metabolism and Pharmacokinetics Research Laboratories (M.O., K.Ko., S.I., K.Ka., T.I.) and R&D Project Management Department (T.H.), Sankyo Co., Ltd., Tokyo, Japan

Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that has been withdrawn from the market because of an increased risk of cardiovascular (CV) events. With a special focus on the arteries, the distribution profiles of radioactivity in rats orally administered [¹⁴C]rofecoxib were investigated in comparison with two other COX-2 inhibitors, [¹⁴C]celecoxib and [¹⁴C]CS-706 (2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole), a novel selective COX-2 inhibitor. Whole-body autoradioluminography and quantitative determination of the tissue concentrations showed that considerable radioactivity is retained by and accumulated in the thoracic aorta of rats after oral administration of [¹⁴C]rofecoxib, but not [¹⁴C]celecoxib or [¹⁴C]CS-706. Acid, organic solvent, and proteolytic enzyme treatments of aorta retaining high levels of radioactivity from [¹⁴C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. In agreement with this result, the radioactivity was found to be highly localized on the elastic fibers in the aorta by microautoradiography. The retention of radioactivity on the elastic fibers was also observed in the aortic arch and the coronary artery. These findings indicate that [¹⁴C]rofecoxib and/or its metabolite(s) are covalently bound to elastin in the arteries. These data are consistent with the suggestion of modified arterial elasticity leading to an increased risk of CV events after long-term treatment with rofecoxib.

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