title: The effect of nabumetone and its principal active metabolite on in vitro human gastric mucosal prostanoid synthesis and platelet function.
abstract: Nabumetone is a novel non-steroidal anti-inflammatory drug (NSAID) which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites which are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of gastric erosion while maintaining its efficacy as an anti-inflammatory drug. We compared the effects of nabumetone and 6-methoxy-2-naphthylacetic acid (6MNA; the principal metabolite of nabumetone) with naproxen and indomethacin on in vitro synthesis of the gastroprotective prostaglandins I2 and E2 by human gastric mucosa. To study the effects of 6MNA on peripheral target tissues the effects of the above NSAIDs on human platelet aggregation and thromboxane A2 synthesis were also studied. Prostanoid synthesis by the human gastric mucosa was inhibited by indomethacin, naproxen and 6MNA (in this order of potency) whereas nabumetone was completely without effect. Platelet aggregation and thromboxane A2 synthesis were similarly inhibited by the NSAIDS (viz. indomethacin greater than naproxen greater than 6MNA greater than nabumetone). These results support the view that nabumetone does not inhibit gastroprotective prostanoid synthesis, whereas its active metabolite 6MNA is an effective inhibitor of prostanoid synthesis in target tissues.
authors.affiliation: Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London.
authors.forename: J Y
authors.initials: JY
authors.lastname: Jeremy
authors.forename: D P
authors.initials: DP
authors.lastname: Mikhailidis
authors.forename: M A
authors.initials: MA
authors.lastname: Barradas
authors.forename: R M
authors.initials: RM
authors.lastname: Kirk
authors.forename: P
authors.initials: P
authors.lastname: Dandona
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D002074:Butanones / Q000494:pharmacology*; D046508:Culture Techniques; D015232:Dinoprostone / Q000096:biosynthesis*; D011464:Epoprostenol / Q000096:biosynthesis*; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D000077430:Nabumetone; D009280:Naphthaleneacetic Acids / Q000494:pharmacology*; D009288:Naproxen / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D009280:Naphthaleneacetic Acids; D013929:Thromboxane B2; D013928:Thromboxane A2; D009288:Naproxen; D015121:6-Ketoprostaglandin F1 alpha; C044612:6-methoxy-2-naphthylacetic acid; D011464:Epoprostenol; D015232:Dinoprostone; D000077430:Nabumetone; D007213:Indomethacin