Investigating Vioxx Toxicity

Oxidation to a maleic anhydride derivative may be a factor in the long-term toxicity of rofecoxib (Vioxx), a new report suggests. This previously unknown reactivity is not shared by other cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex), valdecoxib (Bextra), and lumiracoxib (Prexige). The hypothesis, if proven true, runs counter to the assumption that other COX-2 inhibitors pose the same risk to humans as Vioxx.

Vioxx was withdrawn from the market last September by its manufacturer, Merck, after a clinical trial indicated that it poses an increased risk of cardiovascular events.

Vioxx is a weak acid, and the anion formed when it releases its acidic proton is highly reactive toward atmospheric oxygen, according to laboratory studies by Harvard University chemists Leleti Rajender Reddy and E. J. Corey. The products are principally a maleic anhydride and lesser amounts of a -hydroxybutenolide [Tetrahedron Lett., published online Dec. 25, 2004, http://dx.doi.org/10.1016/j.tetlet.2004.12.055].

According to the authors, the maleic anhydride has not been reported as a Vioxx metabolite. They suggest that some of it may survive long enough in vivo to react with the nucleophilic groups of biomolecules and tissues. "The consequences of this may be a low-level chronic toxicity that is cumulative and possibly dangerous over periods of many months. It is perhaps not irrelevant that the cardiotoxicity of Vioxx was not apparent from short-term (one year or less) studies," they write.

Merck's withdrawal of Vioxx has cast doubts on other COX-2 inhibitors in the market or in development. However, as the authors point out, the formation of an oxygen-reactive anion is unique to Vioxx. The difference in the structures of Vioxx and other COX-2 inhibitors has been "overlooked in the medical and general literature," they write.

In a footnote, the authors say that they have disclosed their findings to the Food & Drug Administration. Corey is a scientific adviser to Pfizer, the maker of Celebrex and Bextra.