RATIONALE N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamine (PX-1), N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide (PX-2), and N-(1-amino-1-oxo-3-phenylpropan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (PX-3) are scheduled synthetic cannabinoids (SCs). Due to the lack of metabolism data and the extensive metabolism of SCs, consumption of these illicit substances is challenging to prove. The aim of this study was to investigate the metabolism of PX-1, PX-2, and PX-3 and propose marker metabolites to confirm their use. METHODS PX-1, PX-2, and PX-3 were incubated in pooled human liver microsomes (HLM) to evaluate the phase I metabolites which were identified using a Q-Exactive hybrid quadrupole-Orbitrap mass spectrometer. Metabolic stability studies were also performed to investigate the half-life and clearance rates using an Agilent 6470A triple quadrupole mass spectrometer. RESULTS The calculated half-lives were 15.1 ± 1.02, 3.4 ± 0.27, and 5.2 ± 0.89 min for PX-1, PX-2, and PX-3, respectively, in HLM. The calculated intrinsic clearance values were 0.046, 0.202, and 0.133 mL/min/mg for PX-1, PX-2, and PX-3, respectively. Four metabolites of PX-1, six metabolites of PX-2, and five phase I metabolites of PX-3 were detected. Oxidative deamination was the common biotransformation between the three compounds and there were no common metabolites. CONCLUSIONS The metabolic profiles of PX-1, PX-2, and PX-3 provide valuable information for the detection of their metabolites in forensic samples.

中文翻译：

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高分辨率大麻在体外对合成大麻素PX-1，PX-2和PX-3的代谢及其在人肝微粒体中的清除率。

理据N-（1-氨基-1-氧代-3-苯基丙-2-基）-1-（5-氟戊基）-1H-吲哚-3-羧胺（PX-1），N-（1-氨基-1 -氧代-3-苯基丙烷-2-基）-1-（5-氟戊基）-1H-吲唑-3-羧酰胺（PX-2）和N-（1-氨基-1-氧代-3-苯基丙烷-2 -yl）-1-（环己基甲基）-1H-吲唑-3-羧酰胺（PX-3）是预定的合成大麻素（SCs）。由于缺乏代谢数据和SC的广泛代谢，这些非法物质的消费难以证明。这项研究的目的是研究PX-1，PX-2和PX-3的代谢，并提出标志物代谢物以确认其用途。方法将PX-1，PX-2和PX-3在人肝微粒体（HLM）中孵育，以评估使用Q-Exactive混合四极杆-Orbitrap质谱仪鉴定的I期代谢产物。还使用Agilent 6470A三重四极杆质谱仪进行了代谢稳定性研究，以研究半衰期和清除率。结果在HLM中，PX-1，PX-2和PX-3的计算半衰期分别为15.1±1.02、3.4±0.27和5.2±0.89 min。对于PX-1，PX-2和PX-3，计算的固有清除率值分别为0.046、0.202和0.133 mL / min / mg。检测到PX-1的四个代谢物，PX-2的六个代谢物和PX-3的五个I期代谢物。氧化脱氨是这三种化合物之间常见的生物转化过程，没有常见的代谢产物。结论PX-1，PX-2和PX-3的代谢谱为法医样品中代谢物的检测提供了有价值的信息。