EFFECTS OF NABUMETONE ON PROSTANOID BIOSYNTHESIS IN HUMANS

Background: The active metabolite of the anti-inflammatory drug nabume tone has been characterized as a selective inhibitor of the inducible prostaglandin H synthase (PGHS). The aim of this study was to investig ate the rate of eicosanoid biosynthesis after oral dosing with nabumet one in nine healthy subjects. Methods: We measured the urinary excreti on of products of platelet (11-dehydro-thromboxane B-2 [TXB(2)]) and r enal (prostaglandin 1F(2 alpha) [PGF(2 alpha)]) arachidonate metabolis m as in vivo indexes of the constitutive PGHS-1 pathway. Moreover, the production of TXB(2) during whole blood clotting was assessed as an i ndex of the cyclooxygenase activity of platelet PGHS-1 ex vivo. Result s: At steady state, nabumetone (500 and 1000 mg daily for 7 days) was associated with statistically significant dose-dependent reduction in the urinary excretion of 11-dehydro-TXB(2) and serum TXB(2) levels by approximately 50% to 70%. However, the drug did not significantly affe ct the urinary excretion of PGF(2 alpha). After discontinuation of nab umetone, urinary 11-dehydro-TXB(2), excretion and whole blood TXB(2) p roduction returned to predrug levels with a similar timecourse that ua s consistent with the elimination half-life of its active metabolite. The daily administration of low-dose aspirin (40 mg), a selective inhi bitor of platelet PGHS-1, caused a cumulative inhibition of urinary 11 -dehydro-TXB(2) and whole blood TXB(2) production that recovered with a timecourse consistent with platelet turnover. Conclusions: Nabumeton e does dose-dependently inhibit the cyclooxygenase activity of platele t PGHS-1 of healthy subjects both in vivo and ex vivo. Thus it is unli kely that its safety profile in patients may be related to selective i nhibition of the inducible PGHS-2.