Human Pharmacology and Clinical Neurosciences Research Group, Hospital del Mar Research Institute-IMIM-Parc de Salut Mar, Barcelona, Spain.
Forensic Sci Int. 2012 May 10;218(1-3):62-7. doi: 10.1016/j.forsciint.2011.10.012. Epub 2011 Oct 22.
Atomoxetine (ATX) is a potent inhibitor of the noradrenaline reuptake transporter approved since 2002 for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults as alternative treatment to methylphenidate. A procedure based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of ATX and its main metabolites (4-hydroxyatomoxetine - 4 hydroxyATX - and N-desmethylatomoxetine - des-methylATX) in hair of one treated child and five treated adolescents. Since hair samples can be easily collected without the need for specials skills and exposing a patient to discomfort, hair testing of ATX and eventually of its metabolites should be useful, especially in case of pediatric patients, to check compliance in a wider time-window. After addition of duloxetine as internal standard, hair samples were overnight digested with 2ml 1M NaOH at 45°C. Then, analytes were extracted from alkaline solution with two different 2ml aliquots of tert-butyl methyl ether. Chromatographic separation was achieved at ambient temperature using a reverse-phase column and a mobile phase of 40% of water-60% 5mM ammonium acetate, 50mM formic acid, 4mM trifluoroacetic acid in acetonitrile-water (85:15, v/v). The mass spectrometer was operated in positive ion mode using multiple reaction monitoring. The method was linear over the concentration range 0.2-50ng/mg hair for the all analytes under investigation, with an intra- and inter-assay imprecision and inaccuracy always less than 20% and an analytical recovery between 33.1% and 76.1%, depending on the considered analyte. Only ATX and 4-hydroxyATX were detected in hair samples with concentrations varying from 0.2 to 2.0ng/mg hair and from 0.3 to 1.0ng/mg, respectively. Notwithstanding the absence of any dose-hair concentration relationship, hair monitoring of ATX and concomitant medications commonly administrated in ADHD children and adolescents can be crucial in verifying long-term compliance to prescribed medication in individuals displaying a non negligible tendency to refuse drugs and to lie on the adherence to therapy as a specific symptom of the disease.
阿托西汀（ATX）是一种有效的去甲肾上腺素再摄取转运体抑制剂，自 2002 年以来，它被批准用于治疗儿童、青少年和成人的注意力缺陷/多动障碍（ADHD），作为替代哌醋甲酯的治疗方法。建立了一种基于液相色谱-串联质谱（LC-MS/MS）的方法，用于测定一名治疗儿童和五名治疗青少年头发中的 ATX 及其主要代谢物（4-羟基阿托西汀-4 羟基 ATX-和 N-去甲基阿托西汀-去甲基 ATX）。由于头发样本可以很容易地收集，不需要特殊技能，也不会使患者感到不适，因此，ATX 及其代谢物的头发检测应该是有用的，特别是对于儿科患者，可以在更宽的时间窗口内检查依从性。在加入度洛西汀作为内标后，头发样本在 45°C 下用 2ml1M NaOH 过夜消化。然后，将碱性溶液中的分析物用两份 2ml 叔丁基甲基醚萃取。在室温下，使用反相柱和 40%水-60%5mM 乙酸铵、50mM 甲酸、4mM 三氟乙酸的乙腈-水（85:15，v/v）作为流动相进行色谱分离。质谱仪以正离子模式运行，采用多重反应监测。该方法在研究的所有分析物的浓度范围为 0.2-50ng/mg 头发时呈线性，内和日间精密度和准确度始终小于 20%，分析回收率在 33.1%-76.1%之间，具体取决于所考虑的分析物。只有 ATX 和 4-羟基 ATX 被检测到，浓度分别为 0.2-2.0ng/mg 头发和 0.3-1.0ng/mg 头发。尽管不存在任何剂量-头发浓度关系，但对 ADHD 儿童和青少年中同时使用的 ATX 和伴随药物进行头发监测对于验证长期遵守规定药物至关重要，因为这些患者有明显的拒绝药物和对治疗的不依从的倾向，这是该疾病的一个特殊症状。
