氟比洛芬酯在健康志愿者体内的效应及代谢转归

The effects and metabolic fate of nitroflurbiprofen in healthy volunteers.

作者信息

Zacharowski Paula, Zacharowski Kai, Donnellan Clare, Johnston Atholl, Vojnovic Ivana, Forte Pablo, Del Soldato Piero, Benjamin Nigel, O'Byrne Sharon

机构信息

William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry.

出版信息

Clin Pharmacol Ther. 2004 Oct;76(4):350-8. doi: 10.1016/j.clpt.2004.05.008.

DOI:10.1016/j.clpt.2004.05.008

PMID:15470334

Abstract

OBJECTIVE

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are a new class of cyclooxygenase (COX) inhibitors. To investigate whether these drugs actually release nitric oxide (NO), we labeled the nitroxy group of nitroflurbiprofen with nitrogen 15 to determine the metabolic fate of this compound in humans.

METHOD

Six healthy volunteers who fasted were given an oral dose of 15 N-nitroflurbiprofen (100 mg). Samples of blood, urine, and gastric headspace gas were taken over a 24-hour period to determine the levels of nitroflurbiprofen, flurbiprofen, total nitrate/nitrite, 15 N-nitrate/nitrite, COX activity, and gastric NO. In a crossover study (1 week apart), a further 6 healthy volunteers who fasted were given an oral dose of nitroflurbiprofen (100 mg) or flurbiprofen (65 mg) and levels of gastric NO were determined.

RESULTS

Nitroflurbiprofen was undetectable in the systemic circulation. Levels of 15 N-nitrate/nitrite (5.2% +/- 1.5% enrichment) and flurbiprofen (2.4 +/- 0.7 microg/mL) peaked at 4 hours in the plasma and gradually decreased thereafter. In unstimulated blood, the plasma levels of thromboxane B 2 (COX-1 activity) were 2 to 3 ng/mL, and after calcium ionophore stimulation, large amounts of thromboxane B 2 were produced (112 +/- 31 ng/mL). Prostaglandin E 2 was undetectable in unstimulated blood. After lipopolysaccharide stimulation, the plasma levels of prostaglandin E 2 increased to 15 +/- 4 ng/mL. The metabolite flurbiprofen inhibited plasma COX-1 activity for the duration of the study period (maximum inhibition at 4 hours), whereas COX-2 activity recovered after 6 hours. In the crossover study, levels of gastric NO were higher in subjects given nitroflurbiprofen, when compared with those given flurbiprofen. (The area under the curve for gastric NO was 435 +/- 107 ppm . h versus 305 +/- 94 ppm . h [95% confidence interval of the difference, 89-172 ppm . h; P < .001]).

CONCLUSION

Nitroflurbiprofen was undetectable in the systemic circulation, suggesting metabolism to 15 N-nitrate/nitrite and flurbiprofen in the presystemic circulation. Levels of gastric NO were significantly higher after ingestion of nitroflurbiprofen than flurbiprofen.

摘要

目的

一氧化氮供体型非甾体抗炎药（NO-NSAIDs）是一类新型的环氧化酶（COX）抑制剂。为研究这些药物是否真的能释放一氧化氮（NO），我们用氮15标记了氟比洛芬的硝氧基，以确定该化合物在人体内的代谢命运。

方法

6名空腹的健康志愿者口服一剂15N-氟比洛芬（100毫克）。在24小时内采集血液、尿液和胃内气体样本，以测定氟比洛芬、氟比洛芬、总硝酸盐/亚硝酸盐、15N-硝酸盐/亚硝酸盐、COX活性和胃内NO的水平。在一项交叉研究中（间隔1周），另外6名空腹的健康志愿者口服一剂氟比洛芬（100毫克）或氟比洛芬（65毫克），并测定胃内NO水平。

结果

在体循环中未检测到氟比洛芬。血浆中15N-硝酸盐/亚硝酸盐（富集率5.2%±1.5%）和氟比洛芬（2.4±0.7微克/毫升）的水平在4小时达到峰值，此后逐渐下降。在未受刺激的血液中，血栓素B₂（COX-1活性）的血浆水平为2至3纳克/毫升，在钙离子载体刺激后，产生了大量的血栓素B₂（112±31纳克/毫升）。在未受刺激的血液中未检测到前列腺素E₂。脂多糖刺激后，前列腺素E₂的血浆水平升至15±4纳克/毫升。代谢产物氟比洛芬在研究期间持续抑制血浆COX-1活性（4小时时抑制作用最强），而COX-2活性在6小时后恢复。在交叉研究中，服用氟比洛芬的受试者胃内NO水平高于服用氟比洛芬的受试者。（胃内NO的曲线下面积为435±107 ppm·h，而服用氟比洛芬的受试者为305±94 ppm·h[差异的95%置信区间为89-172 ppm·h；P<.001]）。