Zhong Shihao, Qin Shiyang, Wang Yuanfeng, Li Huan, Wang Xiaoyi, Chai Tianruomei, Lu Jianghai
Food and Drug Anti-doping Laboratory, China Anti-doping Agency, 1st Anding Road, Chaoyang District, 100029 Beijing, China.
The Criminal Investigation Department of Beijing Public Security Bureau, Key Laboratory of Forensic Toxicology, Ministry of Public Security, 1st Longgang Road, Haidian District, Beijing 100085, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2025 Jan 1;1250:124374. doi: 10.1016/j.jchromb.2024.124374. Epub 2024 Nov 21.
Etomidate is a common non-barbiturate anesthetic with psychoactivity, and metomidate, a structural modifier of etomidate, also has the same psychoactive effect, and the abuse of both has gradually intensified. In this study, etomidate, metomidate and their metabolic profiles with 4 days postfertilization (4dpf) zebrafish, 4 months postfertilization (4mpf) zebrafish, human liver microsomes (HLMs) and human liver S9 fraction were investigated using Liquid chromatography with high resolution mass spectrometry (LC-HRMS) for the first time. 14 etomidate metabolites and 11 metomidate metabolites were found, and the related metabolic pathways included monohydroxylation, dihydroxylation, dehydrogenation, N-dealkylation, O-dealkylation, oxidation, N-glucuronidation, O-glucuronidation and combination. Etomidate acid (E6 and M6) was considered a common biomarker for monitoring the abuse of etomidate and its analogues. Two characteristic metabolites (E4 and M4) could be used as biomarkers to monitor etomidate or metomidate abuse, respectively. Dealkylation, hydroxylation and glucuronidation were the main metabolic pathways of etomidate and metomidate. The differences in metabolic profiles of the three metabolic models were also compared for the first time. The results of this study can provide important reference for the detection of target compounds against the abuse of etomidate and metomidate, and the metabolic analysis of similar substances.
依托咪酯是一种常见的具有精神活性的非巴比妥类麻醉剂，而依托咪酯的结构修饰物甲硫咪唑也具有相同的精神活性作用，且两者的滥用情况都在逐渐加剧。在本研究中，首次使用液相色谱-高分辨质谱（LC-HRMS）对依托咪酯、甲硫咪唑及其在受精后4天（4dpf）斑马鱼、受精后4个月（4mpf）斑马鱼、人肝微粒体（HLMs）和人肝S9组分中的代谢谱进行了研究。共发现14种依托咪酯代谢物和11种甲硫咪唑代谢物，相关代谢途径包括单羟基化、二羟基化、脱氢、N-脱烷基化、O-脱烷基化、氧化、N-葡萄糖醛酸化、O-葡萄糖醛酸化及结合反应。依托咪酯酸（E6和M6）被认为是监测依托咪酯及其类似物滥用的常见生物标志物。两种特征性代谢物（E4和M4）可分别用作监测依托咪酯或甲硫咪唑滥用的生物标志物。脱烷基化、羟基化和葡萄糖醛酸化是依托咪酯和甲硫咪唑的主要代谢途径。本研究还首次比较了三种代谢模型代谢谱的差异。本研究结果可为针对依托咪酯和甲硫咪唑滥用的目标化合物检测及类似物质的代谢分析提供重要参考。
