同时评估药物与低萃取和高萃取阿片类药物的相互作用:应用帕瑞克西布对芬太尼和阿芬太尼药代动力学和药效学的影响。

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易卜拉欣AE, Feldman J, Karim A, Kharasch ED

同时评估药物与低萃取和高萃取阿片类药物的相互作用:应用帕瑞克西布对芬太尼和阿芬太尼药代动力学和药效学的影响。

麻醉学。2003四月;98(4):853-61。

PubMed ID

12657846 (PubMed视图

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摘要

背景:Parecoxib是一种肠外环氧合酶-2 (COX-2)抑制剂，用于围手术期镇痛。它是一种非活性前药，在体内水解为活性抑制剂valdecoxib，是肝细胞色素P450 3A4 (CYP3A4)的底物;因此，可能存在与其他CYP3A底物的代谢相互作用。本研究比较了帕瑞昔布对CYP3A底物芬太尼和阿芬太尼的药代动力学和药效学的影响。阿芬太尼是一种低萃取的药物，具有清除率，对药物相互作用高度敏感;芬太尼是一种高萃取的药物，因此理论上不那么容易受到伤害。因此，我们也验证了提取比例影响这些阿片类药物肝脏代谢改变的后果的假设。方法:在获得机构审查委员会批准的书面知情同意后，12名22至40岁的健康志愿者被纳入研究。该方案为随机、双盲、平衡、安慰剂对照、三期(安慰剂、帕瑞昔布或曲利安霉素预处理)交叉研究。受试者同时接受阿芬太尼(15微克/千克)和芬太尼(5微克/千克; 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.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
Parecoxib	细胞色素P450 3A4	蛋白质	人类	未知的	底物	细节
Valdecoxib	细胞色素P450 3A4	蛋白质	人类	未知的	底物	细节