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Effects of nabumetone on prostanoid biosynthesis in humans
Author(s) -
Cipollone Francesco,
Ganci Antonina,
Panara Maria R.,
Greco Anita,
Cuccurullo Franco,
Patrono Carlo,
Patrignani Paola
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90251-1
Subject(s) - nabumetone , chemistry , cyclooxygenase , ex vivo , metabolite , medicine , thromboxane b2 , pharmacology , endocrinology , platelet , sulfinpyrazone , thromboxane a2 , whole blood , prostaglandin , excretion , urinary system , eicosanoid , eicosanoid metabolism , arachidonic acid , biochemistry , in vitro , enzyme , nonsteroidal
Background The active metabolite of the anti‐inflammatory drug nabumetone has been characterized as a selective inhibitor of the inducible prostaglandin H synthase (PGHS). The aim of this study was to investigate the rate of eicosanoid biosynthesis after oral dosing with nabumetone in nine healthy subjects. Methods We measured the urinary excretion of products of platelet (11‐dehydro‐thromboxane B 2 [TXB 2 ]) and renal (prostaglandin 1F 2α [PGF 2α ]) arachidonate metabolism as in vivo indexes of the constitutive PGHS‐1 pathway. Moreover, the production of TXB 2 during whole blood clotting was assessed as an index of the cyclooxygenase activity of platelet PGHS‐1 ex vivo. Results 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 affect the urinary excretion of PGF 2α . After discontinuation of nabumetone, urinary 11‐dehydro‐TXB 2 excretion and whole blood TXB 2 production returned to predrug levels with a similar timecourse that was consistent with the elimination half‐life of its active metabolite. The daily administration of low‐dose aspirin (40 mg), a selective inhibitor 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 Nabumetone does dose‐dependently inhibit the cyclooxygenase activity of platelet PGHS‐1 of healthy subjects both in vivo and ex vivo. Thus it is unlikely that its safety profile in patients may be related to selective inhibition of the inducible PGHS‐2. Clinical Pharmacology & Therapeutics (1995) 58 , 335–341; doi: