BACKGROUND: PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) and 5F-PB-22 (1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid) are new synthetic cannabinoids with a quinoline substructure and the first marketed substances with an ester bond linkage. No human metabolism data are currently available, making it difficult to document PB-22 and 5F-PB-22 intake from urine analysis, and complicating assessment of the drugs' pharmacodynamic and toxicological properties. METHODS: We incubated 10 mumol/l PB-22 and 5F-PB-22 with pooled cryopreserved human hepatocytes up to 3 h and analyzed samples on a TripleTOF 5600+ high-resolution mass spectrometer. Data were acquired via TOF scan, followed by information-dependent acquisition triggered product ion scans with mass defect filtering (MDF). The accurate mass full scan MS and MS/MS metabolite datasets were analyzed with multiple data processing techniques, including MDF, neutral loss and product ion filtering. RESULTS: The predominant metabolic pathway for PB-22 and 5F-PB-22 was ester hydrolysis yielding a wide variety of (5-fluoro)pentylindole-3-carboxylic acid metabolites. Twenty metabolites for PB-22 and 22 metabolites for 5F-PB-22 were identified, with the majority generated by oxidation with or without glucuronidation. For 5F-PB-22, oxidative defluorination occurred forming PB-22 metabolites. Both compounds underwent epoxide formation followed by internal hydrolysis and also produced a cysteine conjugate. CONCLUSION: Human hepatic metabolic profiles were generated for PB-22 and 5F-PB-22. Pentylindole-3-carboxylic acid, hydroxypentyl-PB-22 and PB-22 pentanoic acid for PB-22, and 5'-fluoropentylindole-3-carboxylic acid, PB-22 pentanoic acid and the hydroxy-5F-PB-22 metabolite with oxidation at the quinoline system for 5F-PB-22 are likely the best targets to incorporate into analytical methods for urine to document PB-22 and 5F-PB-22 intake.

中文翻译：

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通过人类肝细胞孵育和高分辨率质谱分析合成大麻素PB-22及其5氟类似物5F-PB-22的代谢。

背景：PB-22（1-戊基-8-喹啉基酯-1H-吲哚-3-羧酸）和5F-PB-22（1-（5-氟戊基）-8-喹啉基酯-1H-吲哚-3-羧酸羧酸）是具有喹啉亚结构的新型合成大麻素，也是市场上第一种具有酯键连接的物质。没有人体新陈代谢的数据是目前已经上市，因此很难从文档尿液分析PB-22和5F-PB-22摄入，复杂的药物的药效学和毒理学性质的评估。方法：我们将10μmol/ l PB-22和5F-PB-22与冷冻保存的人类肝细胞孵育长达3小时，并在TripleTOF 5600+高分辨率质谱仪上分析样品。数据经由TOF扫描取得，然后过滤以质量缺陷相关信息获取触发产物离子扫描（MDF）。使用多种数据处理技术（包括MDF，中性损失和产物离子过滤）对准确的质量全扫描MS和MS / MS代谢物数据集进行了分析。结果：PB-22和5F-PB-22的主要代谢途径是酯水解，产生多种（5-氟）戊基吲哚-3-羧酸代谢产物。鉴定了PB-22的20种代谢物和5F-PB-22的22种代谢物，其中大多数是通过在有或没有葡萄糖醛酸化的情况下氧化而产生的。对于5F-PB-22，发生氧化脱氟形成PB-22的代谢物。两种化合物都经历环氧化物形成，然后进行内部水解，并且还产生了半胱氨酸缀合物。结论：PB-22和5F-PB-22产生人肝代谢图谱。戊烯吲哚-3-羧酸，PB-22的羟基戊基PB-22和PB-22戊酸，