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 COI. 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 greater than naproxen greater than 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.
Dandona
P
P
Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London, England.
Jeremy
J Y
JY
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D002074:Butanones / Q000378:metabolism / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D000077430:Nabumetone; D009288:Naproxen / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011453:Prostaglandins; D013928:Thromboxane A2; D009288:Naproxen; D000077430:Nabumetone; D007213:Indomethacin