超高效液相色谱－串联质谱检测血浆抗精神分裂症药物浓度方法学的建立及药物浓度参考范围的评价

Ultra-high performance liquid chromatography tandem mass spectrometry method for detection of anti-schizophrenic drugs and the evaluation of their therapeutic reference ranges

目的利用超高效液相色谱－串联质谱（UPLC－MS/MS）建立一种检测抗精神分裂症药物浓度的方法，检测血浆阿立哌唑、氨磺必利、奥氮平、帕利哌酮和齐拉西酮的浓度，并且对药物浓度的参考范围进行评价。方法方法学建立及评价。根据美国食品药品监督管理局和美国临床实验室标准协会相关指南，评估所建立UPLC－MS/MS方法学的选择性、准确度、精密度、稳定性和线性范围。通过分析253份临床标本的检测结果，其中男107例（36.2±17.1）岁，女146例（34.2±15.6）岁根据新版德国精神类药物浓度监控指南中推荐药物治疗的参考区间，评估中国患者的符合情况。结果本研究建立的UPLC－MS/MS可同时检测五种抗精神分裂症药物浓度。阿立哌唑、氨磺必利、奥氮平、齐拉西酮和帕利哌酮的定量限（LOQ）分别为3.0、0.1、0.3、9.0和0.3 ng/ml，具有较高的灵敏度。五种药物在相应浓度范围内线性相关系数均〉0.997 7，日内及日间精密度均小于11.1%，回收率为86.2%～104.8%。所测临床标本中阿立哌唑（255.5±121.8）ng/ml、帕利哌酮（37.9±20.0）ng/ml、奥氮平（45.8±21.9）ng/ml和齐拉西酮（70.2±41.8）ng/ml的浓度区间与指南中推荐参考区间呈良好的一致性。对于氨磺必利，本研究所得浓度水平（445.2±231.5）ng/ml明显高于指南中推荐水平（100～320 ng/ml）。结论本研究成功建立了同时分析多种药物的UPLC－MS/MS方法，且可应用于临床抗精神分裂症药物浓度监控。

ObjectiveA highly feasible and reliable ultra-high performance liquid chromatography tandem mass spectrometry （UPLC-MS/MS）method was presented for therapeutic drug monitoring of five anti-schizophrenic drugs （aripiprazole, amisulpride, olanzapine, paliperidone and ziprasidone） simultaneously and the reference range of plasma concentration was investigated.Methodsestablishment and evaluation. The selectivity, accuracy, precision, stability and linear range of established UPLC-MS/MS method were evaluated according to FDA and CLSI. After a ten-month clinical application, a retrospective analysis of 253 positive samples was carried out to investigate conformance of the AGNP therapeutic reference range for Chinese patients.ResultsThe five anti-schizophrenic drugs could be simultaneously measured by the established UPLC-MS/MS within 6 minutes. The LOQs were 0.1 to 9.0 ng/ml. The correlation coefficients were all higher than 0.997 7. The intra-day and inter-day precisions were less than 11.1%, and the recoveries ranged from 86.2% to 104.8%. The clinical results suggested the good consistency in reference range with AGNP for olanzapine, aripiprazole, paliperidone and ziprasidone. While for amisulpride, the plasma concentration level （445.2±231.5） ng/ml was significantly higher than the AGNP-recommended range （100-320） ng/ml.ConclusionThe established UPLC-MS/MS method was very suitable for monitoring anti-schizophrenic drugs.（Chin J Lab Med, 2017, 40： 787-792）