Danaceau Jonathan P, Wood Michelle, Ehlers Melissa, Rosano Thomas G
Waters Corporation, Milford, MA, USA.
Waters Corporation, Wilmslow, UK.
Clin Mass Spectrom. 2020 Oct 28;18:38-47. doi: 10.1016/j.clinms.2020.10.003. eCollection 2020 Nov.
The opioid crisis is linked to an increased misuse of fentanyl as well as fentanyl analogs that originate from the illicit drug market. Much of our current understanding of fentanyl and fentanyl analog use in our communities comes from postmortem toxicology findings. In the clinical settings of addiction medicine and pain management, where the opioid abuse potential is high, the use of fentanyl, as well as specific fentanyl analogs, may be underestimated due to limited plasma testing and limited availability of assays with suitable analytical sensitivity and selectivity to detect misuse of fentanyls. We report plasma and blood assays for 17 fentanyls (these include fentanyl, fentanyl analogs, fentanyl metabolites and synthetic precursors) in clinical, and medical examiner, casework. A mixed-mode solid phase extraction of diluted plasma or precipitated blood was optimized for maximum recovery of the fentanyls with minimized matrix effects. Analysis was performed using a Waters ACQUITY UPLC I-Class interfaced with a Waters Xevo TQ-S micro tandem quadrupole mass spectrometer. Method parameters were optimized and validated for precision, accuracy, carryover, linearity and matrix effects. Application studies were performed in postmortem blood obtained in 44 fentanyl-related fatalities and in serial plasma samples from 18 surgical patients receiving intravenous fentanyl therapy while undergoing parathyroidectomy. Fentanyls found in postmortem cases included fentanyl, norfentanyl, despropionyl-fentanyl (4-ANPP), beta-hydroxy fentanyl (β-OH fentanyl), acetyl fentanyl, acetyl norfentanyl, methoxyacetyl fentanyl, furanyl fentanyl, cyclopropyl fentanyl, and para-fluorobutyryl fentanyl, with fentanyl, norfentanyl, 4-ANPP and β-OH fentanyl predominating in frequency. Fentanyl concentrations ranged from 0.2 to 56 ng/mL and fentanyl was nearly always found with 4-ANPP, norfentanyl and β-OH fentanyl. Concentrations of other fentalogs ranged from <1 to 84 ng/mL (extrapolated). In the surgical cases, fentanyl was detected and quantified along with norfentanyl and β-OH fentanyl, but without detection of 4-ANPP in any of the samples. The association and relative concentrations of β-OH fentanyl, fentanyl and norfentanyl in the postmortem and clinical studies indicated a metabolic, rather than an illicit, source of β-OH fentanyl.
阿片类药物危机与芬太尼以及源自非法毒品市场的芬太尼类似物滥用增加有关。我们目前对社区中芬太尼和芬太尼类似物使用情况的了解大多来自尸检毒理学结果。在成瘾医学和疼痛管理的临床环境中，阿片类药物滥用可能性很高，由于血浆检测有限以及缺乏具有合适分析灵敏度和选择性以检测芬太尼滥用情况的检测方法，芬太尼以及特定芬太尼类似物的使用情况可能被低估。我们报告了用于临床和法医案件工作中17种芬太尼（包括芬太尼、芬太尼类似物、芬太尼代谢物和合成前体）的血浆和血液检测方法。对稀释血浆或沉淀血液进行混合模式固相萃取，以实现芬太尼的最大回收率并将基质效应降至最低。使用与沃特世Xevo TQ-S微串联四极杆质谱仪联用的沃特世ACQUITY UPLC I-Class进行分析。对方法参数进行了优化和验证，包括精密度、准确度、残留、线性和基质效应。在44例与芬太尼相关的死亡病例的尸检血液以及18例接受静脉芬太尼治疗的甲状旁腺切除手术患者的系列血浆样本中进行了应用研究。尸检病例中发现的芬太尼包括芬太尼、去甲芬太尼、去丙酰芬太尼（4-ANPP）、β-羟基芬太尼（β-OH芬太尼）、乙酰芬太尼、乙酰去甲芬太尼、甲氧基乙酰芬太尼、呋喃基芬太尼、环丙基芬太尼和对氟丁酰芬太尼，其中芬太尼、去甲芬太尼、4-ANPP和β-OH芬太尼出现频率最高。芬太尼浓度范围为0.2至56 ng/mL，且芬太尼几乎总是与4-ANPP、去甲芬太尼和β-OH芬太尼同时存在。其他芬太尼类似物的浓度范围为<1至84 ng/mL（推算值）。在手术病例中，检测并定量了芬太尼以及去甲芬太尼和β-OH芬太尼，但在任何样本中均未检测到4-ANPP。尸检和临床研究中β-OH芬太尼、芬太尼和去甲芬太尼的关联及相对浓度表明，β-OH芬太尼来源于代谢而非非法途径。
