Received for publication February 21, 2006.
Revised April 20, 2006.
Accepted for publication May 2, 2006.

Covalent binding of radioactivity from [¹⁴C]rofecoxib, but not [¹⁴C]celecoxib or [¹⁴C]CS-706, to the arterial elastin of rats

Abstract

Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor which has been withdrawn from the market due to an increased risk of cardiovascular (CV) events.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, 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.

Key words: adverse drug reactions, anti-inflammatory drugs, covalent drug binding, cyclooxygenases, drug distribution, drug toxicity, non-steroidal anti-inflammatory drugs

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