Cipollone F, Ganci A, Panara M R, Greco A, Cuccurullo F, Patrono C, Patrignani P
Department of Medicine, University of Chieti G. D'Annunzio School of Medicine, Italy.
Clin Pharmacol Ther. 1995 Sep;58(3):335-41. doi: 10.1016/0009-9236(95)90251-1.
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.
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.
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.
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.
抗炎药萘丁美酮的活性代谢产物已被鉴定为诱导型前列腺素H合成酶（PGHS）的选择性抑制剂。本研究的目的是调查9名健康受试者口服萘丁美酮后类花生酸生物合成的速率。
我们测量了血小板（11-脱氢血栓素B2 [TXB2]）和肾脏（前列腺素IF2α [PGF2α]）花生四烯酸代谢产物的尿排泄量，作为组成型PGHS-1途径的体内指标。此外，评估全血凝血过程中TXB2的产生，作为体外血小板PGHS-1环氧化酶活性的指标。
在稳态时，萘丁美酮（每日500和1000 mg，共7天）与11-脱氢-TXB2的尿排泄量和血清TXB2水平在统计学上显著的剂量依赖性降低相关，降低约50%至70%。然而，该药物对PGF2α的尿排泄量没有显著影响。停用萘丁美酮后，尿11-脱氢-TXB2排泄量和全血TXB2产生量以与其活性代谢产物消除半衰期一致的相似时间进程恢复到用药前水平。每日给予低剂量阿司匹林（40 mg），一种血小板PGHS-1的选择性抑制剂，导致尿11-脱氢-TXB2和全血TXB2产生的累积抑制，其恢复时间进程与血小板更新一致。
萘丁美酮在体内和体外均剂量依赖性地抑制健康受试者血小板PGHS-1的环氧化酶活性。因此，其在患者中的安全性概况不太可能与诱导型PGHS-2的选择性抑制有关。
