Jang Moonhee, Kim In Sook, Park Yu Na, Kim Jihyun, Han Inhoi, Baeck Seungkyung, Yang Wonkyung, Yoo Hye Hyun
National Forensic Service, 139 Jiyang-ro, Yangcheon-gu, Seoul, 158-707, Republic of Korea.
Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University, Ansan, Gyeonggi-do, 426-791, Republic of Korea.
Anal Bioanal Chem. 2016 Jan;408(2):503-16. doi: 10.1007/s00216-015-9116-1. Epub 2015 Oct 29.
Recently, use of novel synthetic cannabinoids has increased greatly despite worldwide efforts to regulate these drugs. XLR-11 ((1-[5'-fluoropentyl]indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone), a fluorinated synthetic cannabinoid with a tetramethylcyclopropyl moiety, has been frequently abused since 2012. XLR-11 produces a number of metabolites in common with its non-fluorinated parent analogue, UR-144 ((1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone). Therefore, it is essential to develop effective urinary markers to distinguish between these drugs. In this study, we investigated the metabolic profile of authentic human urine specimens from suspected users of XLR-11 using liquid chromatography-quadrupole time-of-flight mass spectrometry. Furthermore, we quantified four potential XLR-11 metabolites by using commercially available reference standards. In vitro metabolism of XLR-11 and UR-144 using human liver microsomes was also investigated to compare patterns of production of hydroxypentyl metabolites. Urine samples were prepared with and without enzymatic hydrolysis, and subjected to solid-phase extraction. We identified 19 metabolites generated by oxidative defluorination, hydroxylation, carboxylation, dehydrogenation, glucuronidation, and combinations of these reactions. Among the identified metabolites, 12 were generated from a cyclopropyl ring-opened XLR-11 degradation product formed during smoking. The XLR-11 metabolite with a hydroxylated 2,4-dimethylpent-1-ene moiety was detected in most specimens after hydrolysis and could be utilized as a specific marker for XLR-11 intake. Quantitative results showed that the concentration ratio of 5- and 4-hydroxypentyl metabolites should also be considered as a useful marker for differentiating between the abuse of XLR-11 and UR-144.
最近，尽管全球都在努力管制新型合成大麻素，但这类物质的使用仍大幅增加。XLR-11（(1-[5'-氟戊基]吲哚-3-基)-(2,2,3,3-四甲基环丙基)甲酮）是一种带有四甲基环丙基部分的氟化合成大麻素，自2012年以来一直被频繁滥用。XLR-11产生的许多代谢产物与其非氟化母体类似物UR-144（(1-戊基吲哚-3-基)-(2,2,3,3-四甲基环丙基)甲酮）相同。因此，开发有效的尿液标志物以区分这些药物至关重要。在本研究中，我们使用液相色谱-四极杆飞行时间质谱法研究了来自疑似XLR-11使用者的真实人类尿液样本的代谢谱。此外，我们使用市售参考标准对四种潜在的XLR-11代谢产物进行了定量。还研究了XLR-11和UR-144在人肝微粒体中的体外代谢，以比较羟基戊基代谢产物的生成模式。尿液样本在有和没有酶水解的情况下进行制备，并进行固相萃取。我们鉴定出了19种由氧化脱氟、羟基化、羧化、脱氢、葡萄糖醛酸化以及这些反应的组合产生的代谢产物。在鉴定出的代谢产物中，有12种是由吸烟过程中形成的开环XLR-11降解产物产生的。水解后，大多数样本中都检测到了带有羟基化2,4-二甲基戊-1-烯部分的XLR-11代谢产物，它可作为XLR-11摄入的特异性标志物。定量结果表明，5-羟基戊基和4-羟基戊基代谢产物的浓度比也应被视为区分XLR-11和UR-144滥用的有用标志物。
