合成大麻素PX-2在体外人肝微粒体中的代谢研究

本文通过体外人肝微粒体代谢模型研究合成大麻素N-(1-氨甲酰基-2-苯基乙基)-1-(5-氟戊基)吲唑-3-甲酰胺(PX-2)的代谢物及代谢途径。在体外人肝微粒体模型中加入1 mg·mL^-1PX-2对照品,模拟人体代谢过程孵育60 min,并利用液相色谱Q Exactive?HF组合型四极杆Orbitrap质谱(LC-QE-HF-Orbitrap-MS)分析Ⅰ、Ⅱ相代谢的位点及其代谢途径。结果显示,PX-2经过代谢共产生18种Ⅰ相体外代谢物和3种葡萄糖醛酸化的Ⅱ相体外代谢物,其中参与Ⅰ相代谢的途径包括酰胺水解、氟代戊烷基侧链氧化脱氟、苄基羟基化和吲唑环羟基化等。根据代谢方式、代谢发生位点以及代谢产物的响应强度,推荐PX-2的酰胺水解代谢物(M1.1)、吲唑环单羟基化代谢物和戊烷基侧链脱氟代谢物为合适的潜在代谢标志物。研究结果可为吸食该类物质的认定及生物检材中该类物质检验方法的建立提供依据。

Metabolism of the synthetic cannabinoid PX-2 in human liver microsomes

This study was performed to determine the metabolic profile of a new illicit drug,PX-2,in human liver microsomes.Q Exactive?HF Quadrupole-Orbitrap LC-MS(LC-QE-HF-Orbitrap-MS)was employed to determine the metabolic sites and pathways of phaseⅠand phase II metabolism.PX-2 was added to a microsomal incubation model to simulate human hepatic metabolism.The results showed that a total of 18 phaseⅠmetabolites and 3 glucuronidated phase II metabolites were generated,with the main metabolic pathways of phaseⅠmetabolism including amide hydrolysis,fluoropentyl oxidative defluorination,benzyl hydroxylation,and carbazole ring hydroxylation.Based on the type and sites of metabolism,phaseⅠmetabolites M1.1(amide hydrolysis),M4.1(carbazole cyclic hydroxylation),and M3.1(oxidative defluorinative hydroxylation)are proposed to be potential poisoning markers.The results of this study provide a basis for identification of related drugs and establishment of testing methods in biological samples.