Metabolism and detection of designer benzodiazepines: a systematic review

Synthesis and illicit use of designer benzodiazepines are growing concerns, with these new psychoactive substances (NPS) posing serious health consequences and new hurdles for toxicologists. Consumption marker identification and characterization is paramount in confirming their use. The benzodiazepine core structure is a fusion of benzene and a seven-membered heterocycle with two nitrogen atoms forming the diazepine ring. Minor variations on the core structure produce different classes of benzodiazepines with marked differences in physiological effects. The present review provides a comprehensive designer benzodiazepines metabolism overview and suggests suitable human consumption biomarkers for toxicology casework. A systematic literature search of PubMed®, ScopusTM, Web of ScienceTM, and Cochrane databases was conducted independently by two coauthors adhering to PRISMA guidelines. Data from 30 in vitro and in vivo models of designer benzodiazepines metabolism from January 2007 to February 2023 were included. 1,4-benzodiazepines (n = 10), 2,3-benzodiazepines (n = 1), triazolo-benzodiazepines (n = 9), and thieno-triazolo-benzodiazepines (n = 3) study design, sample pretreatment, analytical techniques, and major metabolites detected in various matrices are addressed. Metabolites following hydroxylation and phase II glucuronide conjugation were the most prevalent analytes. N-Glucuronidation of parent azole-fused benzodiazepines, and nitro-reduced and N-acetylated metabolites of nitro-containing designer benzodiazepines were also common. From these data, we propose a generic metabolic pathway for designer benzodiazepines. The sporadic illicit market presents challenges in toxicological casework and necessitates comprehensive biomarker investigations, especially in cases with legal implications. There are few metabolism data for many designer benzodiazepines, emphasizing the need for research focusing on closing these gaps.

设计类苯二氮䓬类药物（designer benzodiazepines）的合成与非法使用问题愈发引人担忧，这类新型精神活性物质（NPS）不仅会造成严重的健康危害，同时也给毒理学家带来了新的研究障碍。识别并表征消费标志物，是确认此类物质使用情况的核心环节。苯二氮䓬类药物的核心结构由苯环与含两个氮原子的七元杂环稠合而成，该七元杂环即为二氮䓬环。核心结构上的微小差异，可生成不同类别的苯二氮䓬类药物，其生理效应存在显著差异。本综述全面概述了设计类苯二氮䓬类药物的代谢情况，并为毒理案件检测推荐了适用的人体消费生物标志物。两名合著者严格遵循PRISMA指南，独立对PubMed®、ScopusTM、Web of ScienceTM及Cochrane数据库开展了系统性文献检索。最终纳入2007年1月至2023年2月期间共30项关于设计类苯二氮䓬类药物代谢的体外与体内模型研究数据。本综述涵盖了1,4-苯二氮䓬类（n=10）、2,3-苯二氮䓬类（n=1）、三唑并苯二氮䓬类（n=9）以及噻吩并三唑并苯二氮䓬类（n=3）的研究设计、样品前处理、分析技术，以及在多种基质中检出的主要代谢产物相关内容。经羟基化及II相葡萄糖醛酸化反应生成的代谢产物，是最为常见的目标分析物。母体唑类稠合苯二氮䓬类药物的N-葡萄糖醛酸化产物，以及含硝基设计类苯二氮䓬类药物的硝基还原代谢物与N-乙酰化代谢产物，同样较为常见。基于上述数据，本研究提出了设计类苯二氮䓬类药物的通用代谢通路。非法市场上此类药物的零散流通，给毒理案件检测工作带来了挑战，因此需要开展全面的生物标志物研究，尤其针对涉及法律纠纷的案件。目前多数设计类苯二氮䓬类药物的代谢数据仍较为匮乏，这凸显了填补此类研究空白的必要性。