新设计药物1-（2,3-dihydro-1H-inden-5-yl）-2-（pyrrolidine-1-yl）butan-1-one（5-PPDI）在人体中的I相代谢产物研究尿。,Forensic science international

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新设计药物1-（2,3-dihydro-1H-inden-5-yl）-2-（pyrrolidine-1-yl）butan-1-one（5-PPDI）在人体中的I相代谢产物研究尿。
Forensic science international Pub Date : 2020-02-29 , DOI: 10.1016/j.forsciint.2020.110214
Ayumu Ishii ₁ , Kosuke Kusakabe ₁ , Noriyuki Kato ₁ , Shin-Ichi Sasaki ₂ , Kenji Tsujikawa ₃ , Takeshi Wada ₄

Affiliation

吡咯烷二酮（PPs）是含有吡咯烷环的合成卡西酮，在世界范围内都广泛使用。最近，已经发表了关于PP的代谢和细胞毒性的许多研究。在这里，我们重点研究包含茚满骨架的新设计药物：1-（2,3-二氢-1H-茚满-5-基）-2-（吡咯烷-1-基）丁丹-1-酮（5-PPDI），因为迄今为止还没有关于茚满型卡西酮的代谢的报道。鉴定人类尿液中的5-PPDI I期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起着非常重要的作用。我们合成了5-PPDI和四种提议的代谢物的分析标准品。通过用乙腈盐析辅助液-液萃取来制备尿液样品。通过液相色谱高分辨率串联质谱法进行所有标准品和尿液样品的分析。结果，我们能够在尿液样本中检测到5-PPDI及其代谢产物。成功分离了两种合成的1-OH代谢物的非对映异构体，在尿液标本中仅观察到一种非对映异构体。据我们所知，这是关于人类体内PPs立体选择性还原的第一份报告。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 I期代谢的三个特征：（1）茚满骨架的羟基化；（2）羰基的立体选择性还原；（3）茚满骨架的羟基化可能比其他任何代谢过程都更优先进行。此外，检测到2'-OH代谢物的几种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期代谢途径，这对于理解具有茚满骨架的其他PP的代谢至关重要。

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Studies on the phase I metabolites of the new designer drug 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidine-1-yl)butan-1-one (5-PPDI) in human urine.

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.

更新日期：2020-02-29

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