Department of Chemistry and Drug Metabolism, National Institute on Drug Abuse, NIH , Baltimore, MD , USA .
Drug Metab Rev. 2015 May;47(2):124-74. doi: 10.3109/03602532.2015.1029635. Epub 2015 Apr 8.
Synthetic cannabinoids (SC), originally developed as research tools, are now highly abused novel psychoactive substances. We present a comprehensive systematic review covering in vivo and in vitro animal and human pharmacokinetics and analytical methods for identifying SC and their metabolites in biological matrices. Of two main phases of SC research, the first investigated therapeutic applications, and the second abuse-related issues. Administration studies showed high lipophilicity and distribution into brain and fat tissue. Metabolite profiling studies, mostly with human liver microsomes and human hepatocytes, structurally elucidated metabolites and identified suitable SC markers. In general, SC underwent hydroxylation at various molecular sites, defluorination of fluorinated analogs and phase II metabolites were almost exclusively glucuronides. Analytical methods are critical for documenting intake, with different strategies applied to adequately address the continuous emergence of new compounds. Immunoassays have different cross-reactivities for different SC classes, but cannot keep pace with changing analyte targets. Gas chromatography and liquid chromatography mass spectrometry assays - first for a few, then numerous analytes - are available but constrained by reference standard availability, and must be continuously updated and revalidated. In blood and oral fluid, parent compounds are frequently present, albeit in low concentrations; for urinary detection, metabolites must be identified and interpretation is complex due to shared metabolic pathways. A new approach is non-targeted HRMS screening that is more flexible and permits retrospective data analysis. We suggest that streamlined assessment of new SC's pharmacokinetics and advanced HRMS screening provide a promising strategy to maintain relevant assays.
合成大麻素（SC）最初是作为研究工具开发的，现在是高度滥用的新型精神活性物质。我们呈现了一个全面的系统综述，涵盖了体内和体外动物和人体药代动力学以及用于识别生物基质中的 SC 及其代谢物的分析方法。SC 研究有两个主要阶段，第一阶段研究了治疗应用，第二阶段研究了与滥用相关的问题。给药研究表明，SC 具有高亲脂性，并分布于脑和脂肪组织中。代谢产物分析研究，主要用人肝微粒体和人肝细胞进行，对代谢产物进行了结构解析，并确定了合适的 SC 标志物。一般来说，SC 在各种分子部位发生羟化、氟化类似物的脱氟以及几乎所有的相 II 代谢产物都是葡萄糖醛酸苷。分析方法对于记录摄入量至关重要，采用了不同的策略来充分解决新化合物的不断出现。免疫测定法对不同的 SC 类别具有不同的交叉反应性，但无法跟上分析物靶标的变化。气相色谱和液相色谱质谱测定法 - 最初只有少数几个，然后是许多分析物 - 可用，但受到参考标准可用性的限制，并且必须不断更新和重新验证。在血液和口腔液中，尽管浓度较低，但通常存在母体化合物；对于尿液检测，必须识别代谢物，并且由于代谢途径相同，解释较为复杂。一种新的方法是非靶向 HRMS 筛选，它更灵活，并且允许进行回顾性数据分析。我们建议简化新 SC 药代动力学的评估和先进的 HRMS 筛选，为维持相关测定提供一种有前途的策略。
