Fatal intoxication by 5F-ADB and diphenidine: Detection, quantification, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q-TOFMS
Fatal intoxication by 5F-ADB and diphenidine: Detection, quantification, and investigation of their main metabolic pathways in humans by LC/MS/MS and LC/Q-TOFMS
复制标题
DOI：
10.1002/dta.2215
复制
发表时间：
2018-02-01
影响因子：
2.9
通讯作者：
Ishii, Akira
中科院分区：
文献类型：
--
作者：
Kusano, Maiko;Zaitsu, Kei;Ishii, Akira
尽管2013年实施了新的全面时间表制度，但新的精神活性物质(NPS)滥用在日本仍然是一个严重的社会问题。我们提出一个致命的中毒案例，涉及5F-ADB(甲基2-[1-(5-fluoropentyl)-1H-indazole-3-carboxamido]-3，3-dimethylbutanoate)和联苯二胺)。在信息依赖采集模式下，用高效液相色谱/四极杆飞行时间质谱仪(LC/Q-TOFMS)对死后血液进行筛查时，只检测到联苯二胺。进一步使用包含NPS和代谢物的内部数据库进行尿液筛查，不仅检测到联苯二胺，还检测到可能的5F-ADB代谢物；随后通过LC/串联质谱仪(LC/MS/MS)进行靶向筛查，可以在死后心脏血液中检测到非常低水平的未改变的5F-ADB。用标准加入法定量，死后血中5F-ADB和联苯二胺的血药浓度分别为0.19+/-0.04 ng/m L和12+/-2.6 ng/m L。对尿代谢物的研究揭示了5F-ADB的酯水解(M1)和氧化脱氟(M2)，以及进一步氧化为羧酸(M3)的途径。还发现了单羟基联苯胺代谢物和双羟基联苯代谢物。本病例证明了对低血浓度药物进行尿代谢物筛选的重要性。已知在N-烷基末端氟化的合成大麻素(SCs)与其非氟化类似物相比显示出更高的大麻素受体亲和力；5F-ADB也不例外，具有较高的CB1受体活性和比(9)-THC和其他早期SCs更强的效力，因此我们怀疑其急性毒性比其他结构相关的SC类似物高。5F-ADB的低血药浓度可能归因于酶和/或非酶降解，对这些可能性的进一步研究正在进行中。
Despite the implementation of a new blanket scheduling system in 2013, new psychoactive substance (NPS) abuse remains a serious social concern in Japan. We present a fatal intoxication case involving 5F-ADB (methyl 2-[1-(5-fluoropentyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate) and diphenidine. Postmortem blood screening by liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/Q-TOFMS) in the information-dependent acquisition mode only detected diphenidine. Further urinary screening using an in-house database containing NPS and metabolites detected not only diphenidine but also possible 5F-ADB metabolites; subsequent targeted screening by LC/tandem mass spectrometry (LC/MS/MS) allowed for the detection of a very low level of unchanged 5F-ADB in postmortem heart blood. Quantification by standard addition resulted in the postmortem blood concentrations being 0.19 +/- 0.04ng/mL for 5F-ADB and 12 +/- 2.6ng/mL for diphenidine. Investigation of the urinary metabolites revealed pathways involving ester hydrolysis (M1) and oxidative defluorination (M2), and further oxidation to the carboxylic acid (M3) for 5F-ADB. Mono- and di-hydroxylated diphenidine metabolites were also found. The present case demonstrates the importance of urinary metabolite screening for drugs with low blood concentration. Synthetic cannabinoids (SCs) fluorinated at the terminal N-alkyl position are known to show higher cannabinoid receptor affinity relative to their non-fluorinated analogues; 5F-ADB is no exception with high CB1 receptor activity and much greater potency than (9)-THC and other earlier SCs, thus we suspect its acute toxicity to be high compared to other structurally related SC analogues. The low blood concentration of 5F-ADB may be attributed to enzymatic and/or non-enzymatic degradation, and further investigation into these possibilities is underway.