Patton Amy L, Seely Kathryn A, Pulla Sharon, Rusch Nancy J, Moran Cindy L, Fantegrossi William E, Knight Laura D, Marraffa Jeanna M, Kennedy Paul D, James Laura P, Endres Gregory W, Moran Jeffery H
Arkansas Department of Health, Public Health Laboratory, Little Rock, Arkansas 72205, United States.
Anal Chem. 2014 Feb 4;86(3):1760-6. doi: 10.1021/ac4036197. Epub 2014 Jan 15.
Opioid abuse involving emerging opioid compounds is a growing public health problem, which was highlighted recently by cases of human morbidity and mortality linked to acetyl fentanyl abuse. Unfortunately, the lack of information available on the toxicology and metabolism of acetyl fentanyl precludes its detection in human samples. The following study was conducted to test a new analytical procedure for the simultaneous quantification of acetyl fentanyl and its predicted metabolite, acetyl norfentanyl, in human urine. Metabolic reference standards and deuterium-labeled internal standards were synthesized for use in an assay that coupled solid-phase extraction (SPE) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The accuracy (% Relative Error <5%) and inter- and intrarun precision (%CV <20%) of this new method resulted in low levels of quantification (∼1 ng/mL). Similar results were obtained using liquid chromatography columns manufactured with phenyl-hexyl and biphenyl stationary phases (r(2) > 0.98). Preliminary human liver microsomal and in vivo rodent studies demonstrated that acetyl fentanyl is metabolized by cytochrome P450s to acetyl norfentanyl. Urine samples from rats treated with a toxic dose of acetyl fentanyl contained high concentrations of acetyl fentanyl and acetyl norfentanyl. Further toxicokinetic studies are required to fully elucidate the metabolic pathways responsible for acetyl fentanyl detoxification and excretion.
涉及新型阿片类化合物的阿片类药物滥用是一个日益严重的公共卫生问题，最近与乙酰芬太尼滥用相关的人类发病和死亡案例凸显了这一问题。不幸的是，由于缺乏关于乙酰芬太尼毒理学和代谢的信息，无法在人体样本中对其进行检测。开展了以下研究，以测试一种同时定量人尿中乙酰芬太尼及其预测代谢物乙酰去甲芬太尼的新分析程序。合成了代谢参考标准品和氘代内标，用于一种将固相萃取（SPE）与液相色谱-串联质谱（LC-MS/MS）相结合的分析方法。这种新方法的准确度（相对误差百分比<5%）以及批间和批内精密度（变异系数百分比<20%）实现了低定量限（约1 ng/mL）。使用由苯基己基和联苯固定相制造的液相色谱柱也获得了类似结果（r(2)>0.98）。初步的人肝微粒体和体内啮齿动物研究表明，乙酰芬太尼通过细胞色素P450s代谢为乙酰去甲芬太尼。用有毒剂量的乙酰芬太尼处理的大鼠的尿液样本中含有高浓度的乙酰芬太尼和乙酰去甲芬太尼。需要进一步开展毒代动力学研究，以全面阐明负责乙酰芬太尼解毒和排泄的代谢途径。
