Scientific Crime Laboratory, Kanagawa Prefectural Police Headquarters, Japan.
Forensic Science Laboratory, Metropolitan Police Department, Japan.
Forensic Sci Int. 2020 May;310:110214. doi: 10.1016/j.forsciint.2020.110214. Epub 2020 Feb 29.
Pyrrolidinophenones (PPs) are synthetic cathinones containing a pyrrolidine ring that are used recreationally worldwide. Recently, many studies on the metabolism and cytotoxicity of PPs have been published. Here, we focus on new designer drug containing an indan skeleton, 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidine-1-yl)butan-1-one (5-PPDI), because there have been no reports to date regarding the metabolism of indan-type cathinones. The identification of 5-PPDI phase I metabolites in human urine enables us to determine whether a person has taken 5-PPDI. This metabolite detection approach plays a very important role in the field of forensic science. We synthesized analytical standards of 5-PPDI and four proposed metabolites. A urine sample was prepared by salting-out assisted liquid-liquid extraction with acetonitrile. Analyses of all standards and the urine sample were performed by liquid chromatography high resolution tandem mass spectrometry. As a result, we were able to detect 5-PPDI and its metabolites in the urine specimen. Two diastereomers of synthesized 1-OH metabolites were successfully separated, and only one diastereomer was observed in the urine specimen. To the best of our knowledge, this is the first report on the stereoselective reduction of PPs in humans. Further, we performed quantitative analyses of 5-PPDI and its metabolites in the urine. We identified three characteristic features of 5-PPDI phase I metabolism: (1) hydroxylation at the indan skeleton, (2) stereoselective reduction of the carbonyl group, and (3) hydroxylation of the indan skeleton possibly proceeding more preferentially than any other metabolization. In addition, several structural isomers and diastereomers of 2'-OH metabolites were detected. Based on these data, we propose phase I metabolic pathways of 5-PPDI, which will be essential in understanding the metabolism of other PPs with an indan skeleton.
吡咯烷苯丙酮（PPs）是一种含有吡咯烷环的合成卡西酮，在全球范围内被娱乐性使用。最近，许多关于 PPs 的代谢和细胞毒性的研究已经发表。在这里，我们专注于一种含有茚烷骨架的新型设计药物，1-(2,3-二氢-1H-茚-5-基)-2-(吡咯烷-1-基)丁-1-酮（5-PPDI），因为迄今为止还没有关于茚型卡西酮代谢的报道。在人尿中鉴定出 5-PPDI 的 I 相代谢物使我们能够确定一个人是否服用了 5-PPDI。这种代谢物检测方法在法医学领域中起着非常重要的作用。我们合成了 5-PPDI 和四个提议的代谢物的分析标准品。通过乙腈盐析辅助液-液萃取制备尿液样品。所有标准品和尿液样品的分析均通过液相色谱高分辨串联质谱法进行。结果，我们能够在尿液标本中检测到 5-PPDI 及其代谢物。合成的 1-OH 代谢物的两种非对映异构体成功分离，而在尿液标本中仅观察到一种非对映异构体。据我们所知，这是关于人类中 PPs 的立体选择性还原的首次报道。此外，我们对尿液中的 5-PPDI 及其代谢物进行了定量分析。我们确定了 5-PPDI 一期代谢的三个特征：（1）茚烷骨架的羟化，（2）羰基的立体选择性还原，（3）茚烷骨架的羟化可能比任何其他代谢更优先进行。此外，还检测到 2'-OH 代谢物的几个结构异构体和非对映异构体。基于这些数据，我们提出了 5-PPDI 的 I 相代谢途径，这对于理解具有茚烷骨架的其他 PPs 的代谢至关重要。
