Abstract In vitro and in vivo metabolism of synthetic cannabinoid, N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluropentyl)-1H-indazole-3-carboxamide (PX-2), has been studied based on human liver microsomes and zebrafish using ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The dd-MS2 spectra technique is used to analysis metabolic sites and pathway by accurate mass measurement in the research process. An animal model of zebrafish in vivo metabolism is established to verify the in vitro metabolism pathway of PX-2. The results indicated that 20 kinds of metabolites were generated in the zebrafish animal model and human liver microsome model. Biotransformations mainly occurred at the amino of the compound, and minor reaction occurred at the pentyl chain and benzyl. We recommend M1.1 (PX-2 amide hydrolysis metabolites), and M3.1 (PX-2 oxidative defluorination and hydroxylation) combined M1.4 (PX-2 Phenylalanine loss) to be the potential poisoning markers.

中文翻译：

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新型合成大麻素 PX-2 在人肝微粒体和斑马鱼中的体外和体内代谢研究

摘要合成大麻素 N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluropentyl)-1H-indazole-3-carboxamide (PX-2 )，已使用超高效液相色谱结合四极杆 Orbitrap 高分辨率质谱 (UHPLC-Q-Orbitrap HRMS) 基于人肝微粒体和斑马鱼进行了研究。dd-MS2光谱技术用于在研究过程中通过精确的质量测量来分析代谢位点和途径。建立斑马鱼体内代谢动物模型，验证PX-2体外代谢途径。结果表明，在斑马鱼动物模型和人肝微粒体模型中产生了20种代谢物。生物转化主要发生在化合物的氨基，戊基链和苄基发生轻微反应。我们推荐 M1.1（PX-2 酰胺水解代谢物）和 M3.1（PX-2 氧化脱氟和羟基化）结合 M1.4（PX-2 苯丙氨酸损失）作为潜在的中毒标志物。