Nonsteroidal Anti-Inflammatory Drug Therapy and Gastric Side Effects: Does Nabumetone Provide a Solution?

Nabumetone is a novel nonsteroidal anti-inflammatory drug (NSAID) which, although a weak cyclo-oxygenase inhibitor (COI), is converted in the liver to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), which is a more potent COL Thus nabumetone may reduce gastric erosion while maintaining its efficacy as an anti-inflammatory drug peripherally. To investigate this novel ‘prodrug’ further we compared the effects of nabumetone and 6-MNA with those of naproxen and indomethacin on the synthesis of the gastroprotective prostaglandins (PG) epoprostenol (I₂) and dinoprostone (E2) by rat and human gastric mucosa in vitro, and ex vivo in the rat. The effect of these NSAIDs on platelet aggregation and thromboxane A₂ (TXA₂) synthesis was also studied. In human and rat gastric mucosa the synthesis of epoprostenol and dinoprostone was inhibited by indomethacin, naproxen and 6-MNA (indomethacin > naproxen > 6-MNA) whereas nabumetone had no effect whatsoever. Platelet aggregation and TXA2 synthesis were inhibited in a similar manner. These results indicate that nabumetone does not inhibit gastroprotective prostaglandins, whereas its active metabolite, 6-MNA, is an effective inhibitor of prostanoid synthesis in target tissues.