PDF(Pubmed)
Abstract：
The recent re-emergence and the increasing popularity of nitazenes, a group of new synthetic opioids (NSO) that belong to the benzimidazole chemical class, has raised public health concerns. As a class of potential opioid analgesic agents whose development was discontinued in the 1960s due to their high potential for abuse, very little is known about their metabolism and physiologic disposition. In the current study, three nitazenes-butonitazene, isotonitazene and protonitaze were incubated in human liver microsomes (HLM), human S9 (HS9) fractions and recombinant cytochrome P450 enzymes. All three nitazenes were rapidly metabolized in both HLM and HS9 with over 95% depletion within 60 min. In HLM, butonitazene, isotonitazene and protonitazene had in vitro intrinsic clearance (CLint) (µL/min/mg protein) values of 309, 221 and 216 respectively compared to 150 of verapamil, the positive control. In HS9, CLint values were 217, 139, and 150 for butonitazene, isotonitazene and protonitazene respectively compared to only 35 for testosterone, the control probe substrate. Putative metabolite identified from this study include products of hydroxylation, desethylation, dealkylation, desethylation followed by dealkylation, and desethylation followed by hydroxylation. The metabolic phenotyping showed CYP2D6, CYP2B6 and CYP2C8 and the major hepatic enzymes responsible for the metabolism of nitazenes. Within 30 min of incubation, CYP2D6 depleted butonitazene (99%), isotonitazene (72%) and butonitazene (100%) significantly. The rapid metabolism of nitazenes may be an important factor in accurate and timely detections and quantitation of the unchanged drugs in human matrices following intoxication or in forensic analysis. The involvement of multiple polymorphic CYPs in their metabolism may play important roles in the susceptibility to intoxication and/or addiction, depending on the activity of the metabolites.
摘要：
最近的重新出现和硝基苯的日益普及，一组属于苯并咪唑化学类的新合成阿片类药物（NSO），引发了公众健康问题。作为一类潜在的阿片类镇痛剂，由于其高滥用潜力而在1960年代停止开发，对它们的代谢和生理倾向知之甚少。在目前的研究中,三种硝基苯-丁二烯，在人肝微粒体（HLM）中孵育等氮氮烯和质子，人S9（HS9）级分和重组细胞色素P450酶。所有三种硝基苯在HLM和HS9中均迅速代谢，在60分钟内消耗超过95％。在HLM中,butonitazene,与150的维拉帕米相比，异单氮嗪和质子氮嗪的体外固有清除率（CLint）（µL/min/mg蛋白）值分别为309、221和216，积极的控制。在HS9中，布托利氮烯的CLint值分别为217、139和150，与睾丸激素的35相比，异氮氮烯和质子氮烯分别为35，控制探针基板。从这项研究中鉴定出的推定代谢物包括羟基化产物，去甲基化,脱烷基化,去甲基化，然后去烷基化，和去乙基化，然后羟基化。代谢表型显示CYP2D6，CYP2B6和CYP2C8以及负责硝基苯代谢的主要肝酶。在孵育30分钟内，CYP2D6贫化的布他氮烯（99%），异单氮烯（72％）和丁氮烯（100％）显着。硝基苯的快速代谢可能是中毒后或法医分析中准确，及时地检测和定量人体基质中不变药物的重要因素。多个多态性CYPs参与其代谢可能在对中毒和/或成瘾的易感性中起重要作用。取决于代谢物的活性。
