使用 UHPLC-MS-QToF 研究人体中合成卡西酮 α-吡咯烷异己酮的代谢。

Metabolism of the Synthetic Cathinone Alpha-Pyrrolidinoisohexanophenone in Humans Using UHPLC--MS-QToF.

机构信息

Department of Forensic Toxicology, Hungarian Institute of Forensic Sciences, H-1087 Budapest Mosonyi street 9. P.O.B.: 314/4, Budapest H-1903, Hungary.

出版信息

J Anal Toxicol. 2023 Mar 24;47(3):253-262. doi: 10.1093/jat/bkac085.

DOI:10.1093/jat/bkac085

PMID:36287060

Abstract

Alpha-pyrrolidinoisohexanophenone (α-PHiP/α-PiHP) is a synthetic drug structurally related to cathine, a natural psychoactive alkaloid, isolated from Khat plant. The α-PiHP is a structural isomer of α-PHP, and both α-PHP and α-PiHP could be considered an analog of α-PVP, a Schedule I drug under the Convention on Psychotropic Substances by the United Nations. This α-pyrrolidinophenone was first reported to European Monitoring of Drug and Drug Addiction by Slovenia in December 2016. In Hungary, it was initially reported in August 2016, and until 2021, it had been detected in seizures only twice and never been identified in biological samples. However, in 2021, its consumption became prevalent in Hungary. This study aims to investigate the α-PiHP metabolites by performing in vitro and in vivo metabolite identification studies of human liver microsome (pHLM), S9 fraction (pS9) and urine samples (from control and users), using liquid chromatography in conjunction with high-resolution mass spectrometry. Ten in vivo urinary metabolites of α-PiHP were tentatively identified and confirmed by in vitro metabolites detected in pHLM and pS9 samples. Among the eight Phase I and the two Phase II metabolites, five were more abundant in urine than the parent compound. The two major metabolites via reduction of the keto moiety (M01) and via oxidation of the pyrrolidine ring combined with aliphatic hydroxylation and keto reduction (M06) were identified. The metabolites via the combination of keto reduction and aliphatic hydroxylation (M04), via ring-opening followed by carboxylation (M09) and via glucuronidation of the keto reduced metabolite (M07) were also dominant. The minor metabolites were one Phase II metabolite (M08), two metabolites via aliphatic hydroxylation (M02 and M03), one metabolite via the combination of keto reduction and oxidation of the pyrrolidine ring (M05) and one metabolite via oxidation of the pyrrolidine ring (M10).

摘要

α-吡咯烷异己基苯酮（α-PHiP/α-PiHP）是一种与卡西酮有关的合成药物，卡西酮是一种从阿拉伯茶植物中分离出来的天然精神活性生物碱。α-PiHP 是 α-PHP 的结构异构体，而 α-PHP 和 α-PiHP 都可以被认为是 α-PVP 的类似物，α-PVP 是联合国《精神药物公约》下的附表 I 药物。这种 α-吡咯烷酮于 2016 年 12 月由斯洛文尼亚首次向欧洲毒品和药物监测中心报告。在匈牙利，它最初于 2016 年 8 月报告，直到 2021 年，它只在缉获物中检测到两次，从未在生物样本中确定。然而，2021 年，它在匈牙利的消费变得普遍。本研究旨在通过进行体外和体内代谢物鉴定研究，使用液相色谱法结合高分辨率质谱法，研究人肝微粒体（pHLM）、S9 级分（pS9）和尿液样本（来自对照和使用者），来研究 α-PiHP 的代谢物。通过在 pHLM 和 pS9 样本中检测到的体外代谢物，初步鉴定并确认了 α-PiHP 的十种体内尿代谢物。在 8 个 I 相和 2 个 II 相代谢物中，有 5 个在尿液中的丰度高于母体化合物。通过酮部分还原（M01）和吡咯烷环氧化与脂肪族羟化和酮还原相结合（M06）鉴定了两种主要代谢物。还鉴定了通过酮还原和脂肪族羟化的组合（M04）、通过开环随后羧化（M09）和通过酮还原代谢物的葡萄糖醛酸化（M07）的代谢物。次要代谢物为一个 II 相代谢物（M08）、两个通过脂肪族羟化的代谢物（M02 和 M03）、一个通过酮还原和吡咯烷环氧化结合的代谢物（M05）和一个通过吡咯烷环氧化的代谢物（M10）。