Effects of nabumetone on prostanoid biosynthesis in humans.
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 B2 [TXB2]) and renal (prostaglandin IF2 alpha [PGF2 alpha]) arachidonate metabolism as in vivo indexes of the constitutive PGHS-1 pathway. Moreover, the production of TXB2 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-TXB2 and serum TXB2 levels by approximately 50% to 70%. However, the drug did not significantly affect the urinary excretion of PGF2 alpha. After discontinuation of nabumetone, urinary 11-dehydro-TXB2 excretion and whole blood TXB2 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-TXB2 and whole blood TXB2 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.
Cipollone
F
F
Department of Medicine, University of Chieti G. D'Annunzio School of Medicine, Italy.
Ganci
A
A
Panara
M R
MR
Greco
A
A
Cuccurullo
F
F
Patrono
C
C
Patrignani
P
P
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism; D002074:Butanones / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015237:Dinoprost / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077430:Nabumetone; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016718:Arachidonic Acid; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D000077430:Nabumetone