同时评估药物的相互作用与低收入和耐光阿片类药物:应用parecoxib对芬太尼的药代学和药效学的影响和alfentanil。

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易卜拉欣AE,费尔德曼J,卡里姆,Kharasch ED

同时评估药物的相互作用与低收入和耐光阿片类药物:应用parecoxib对芬太尼的药代学和药效学的影响和alfentanil。

麻醉学。2003年4月,98 (4):853 - 61。

PubMed ID

12657846 (在PubMed

]

文摘

背景:Parecoxib是肠外cyclooxygenase-2 (cox - 2)抑制剂用于围手术期镇痛。这是一个不活跃的前药水解活性抑制剂valdecoxib体内,为肝基质细胞色素P450 3 a4 (CYP3A4);因此,存在一个潜在的与其他CYP3A基质代谢的相互作用。本研究确定的影响parecoxib的药物动力学和药效学CYP3A基质与CYP3A抑制剂相比芬太尼和alfentanil troleandomycin。Alfentanil low-extraction药物有间隙,极易受药物相互作用;芬太尼是一种耐光的药物,从而在理论上是那么脆弱。因此,我们还测试了萃取率的影响的假设这些阿片类药物的肝代谢改变的结果。方法:机构审查委员会批准了之后,,获得知情同意,12 22 - 40-yr-old健康志愿者参与了这项研究。协议是一个随机、双盲、平衡、安慰剂对照,结束(安慰剂,parecoxib或troleandomycin预处理)交叉。受试者接受alfentanil (15 microg /公斤)和芬太尼(5 microg /公斤; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores. RESULTS: There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin. CONCLUSIONS: Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.

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药物酶

药物	酶	类	生物	药理作用	行动
Parecoxib	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
Valdecoxib	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节