Liu Dan, An Zhuoling, Li Pengfei, Chen Yanhua, Zhang Ruiping, Liu Lihong, He Jiuming, Abliz Zeper
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100050 P. R. China
Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University Beijing 100020 P. R. China
RSC Adv. 2020 May 13;10(31):18305-18314. doi: 10.1039/d0ra02406f. eCollection 2020 May 10.
Neurotransmitters (NTs) are specific endogenous metabolites that act as "messengers" in synaptic transmission and are widely distributed in the central nervous system. Olanzapine (OLZ), a first-line antipsychotic drug, plays a key role in sedation and hypnosis, but, it presents clinical problems with a narrow therapeutic window, large individual differences and serious adverse effects, as well as an unclear mechanism . Herein, a simultaneous targeted NT quantification and nontargeted metabolomics method was developed and validated for pharmacometabolomics analysis of OLZ by using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Considering the low physiological concentrations of NTs, a full MS scan and target selective ion monitoring (tSIM) scan were combined for nontargeted metabolomics and targeted NT quantification, respectively. By using this strategy, NTs at a very low physiological concentration can be accurately detected and quantified in biological samples by tSIM scans. Moreover, simultaneously nontargeted profiling was also achieved by the full MS scan. The newly established UPLC-HRMS method was further used for the pharmacometabolomics study of OLZ. Statistical analysis revealed that tryptophan, 5-hydroxytryptophan, 5-hydroxytryptamine, γ-aminobutyric acid were significantly downregulated, while tyrosine was significantly upregulated, which suggested that OLZ could promote the downstream phase II reaction of 5-hydroxytryptamine, inhibit tyrosine hydroxylase activity, and increase the activity of γ-aminobutyric acid transaminase. In conclusion, this method could provide novel insights for revealing the pharmacodynamic effect and mechanism of antipsychotic drugs.
神经递质（NTs）是一类特定的内源性代谢产物，在突触传递中充当“信使”，广泛分布于中枢神经系统。奥氮平（OLZ）是一线抗精神病药物，在镇静和催眠方面起关键作用，但其治疗窗窄、个体差异大、不良反应严重，且作用机制尚不明确。在此，我们开发并验证了一种同时进行靶向NTs定量和非靶向代谢组学的方法，用于采用超高效液相色谱-高分辨率质谱联用技术（UPLC-HRMS）对OLZ进行药物代谢组学分析。考虑到NTs的生理浓度较低，分别将全扫描质谱和目标选择性离子监测（tSIM）扫描用于非靶向代谢组学和靶向NTs定量。通过该策略，可通过tSIM扫描在生物样品中准确检测和定量极低生理浓度的NTs。此外，全扫描质谱同时也实现了非靶向分析。新建立的UPLC-HRMS方法进一步用于OLZ的药物代谢组学研究。统计分析表明，色氨酸、5-羟色氨酸、5-羟色胺、γ-氨基丁酸显著下调，而酪氨酸显著上调，这表明OLZ可促进5-羟色胺的下游Ⅱ相反应，抑制酪氨酸羟化酶活性，并增加γ-氨基丁酸转氨酶的活性。总之，该方法可为揭示抗精神病药物的药效和作用机制提供新的见解。
