Negreira Noelia, Erratico Claudio, Kosjek Tina, van Nuijs Alexander L N, Heath Ester, Neels Hugo, Covaci Adrian
Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium.
Anal Bioanal Chem. 2015 Jul;407(19):5803-16. doi: 10.1007/s00216-015-8763-6. Epub 2015 May 27.
The aim of the present study was to identify the in vitro Phase I and Phase II metabolites of three new psychoactive substances: α-pyrrolidinovalerophenone (α-PVP), methylenedioxypyrovalerone (MDPV), and methedrone, using human liver microsomes and human liver cytosol. Accurate-mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry. Six Phase I metabolites of α-PVP were identified, which were formed involving reduction, hydroxylation, and pyrrolidine ring opening reactions. The lactam compound was the major metabolite observed for α-PVP. Two glucuronidated metabolites of α-PVP, not reported in previous in vitro studies, were further identified. MDPV was transformed into 10 Phase I metabolites involving reduction, hydroxylation, and loss of the pyrrolidine ring. Also, six glucuronidated and two sulphated metabolites were detected. The major metabolite of MDPV was the catechol metabolite. Methedrone was transformed into five Phase I metabolites, involving N- and O-demethylation, hydroxylation, and reduction of the ketone group. Three metabolites of methedrone are reported for the first time. In addition, the contribution of individual human CYP enzymes in the formation of the detected metabolites was investigated.
本研究的目的是利用人肝微粒体和人肝细胞溶质，鉴定三种新型精神活性物质：α-吡咯烷戊酮（α-PVP）、亚甲基二氧吡咯戊酮（MDPV）和甲麻黄碱的体外Ⅰ相和Ⅱ相代谢产物。使用液相色谱-四极杆飞行时间质谱法获得代谢产物的精确质量谱。鉴定出α-PVP的6种Ⅰ相代谢产物，其形成涉及还原、羟基化和吡咯烷环开环反应。内酰胺化合物是观察到的α-PVP的主要代谢产物。进一步鉴定出α-PVP的两种葡萄糖醛酸化代谢产物，这在以前的体外研究中未报道。MDPV转化为10种Ⅰ相代谢产物，涉及还原、羟基化和吡咯烷环的丢失。此外，还检测到6种葡萄糖醛酸化代谢产物和2种硫酸化代谢产物。MDPV的主要代谢产物是儿茶酚代谢产物。甲麻黄碱转化为5种Ⅰ相代谢产物，涉及N-去甲基化、O-去甲基化、羟基化和酮基还原。首次报道了甲麻黄碱的3种代谢产物。此外，还研究了个体人CYP酶在检测到的代谢产物形成中的作用。
