Schaefer Nadine, Helfer Andreas G, Kettner Mattias, Laschke Matthias W, Schlote Julia, Ewald Andreas H, Meyer Markus R, Menger Michael D, Maurer Hans H, Schmidt Peter H
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421, Homburg (Saar), Germany.
Department of Experimental and Clinical Toxicology, Saarland University, Building 46, D-66421, Homburg (Saar), Germany.
Drug Test Anal. 2017 Apr;9(4):613-625. doi: 10.1002/dta.1995. Epub 2016 Jun 22.
The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd.
了解合成大麻素（SCs）的药代动力学（PK）特性对于解释例如在中毒个体中发现的分析结果很重要。在缺乏来自对照研究的人体数据的情况下，必须建立阐明SCs PK的动物模型。对能提供大量生物流体样本的猪进行了测试，以预测人体PK数据。在此背景下，除了Δ-四氢大麻酚（THC）之外，还阐明了两种模型SCs的代谢命运，即4-乙基萘-1-基-（1-戊基吲哚-3-基）甲酮（JWH-210）和2-（4-甲氧基苯基）-1-（1-戊基吲哚-3-基）甲酮（RCS-4）。静脉注射这些化合物后，通过液相色谱-高分辨率质谱法分析每小时收集的猪尿液。观察到以下途径：对于JWH-210，在乙基侧链或戊基链上进行羟基化以及它们的组合，随后进行葡萄糖醛酸化；对于RCS-4，在甲氧基苯基部分或戊基链上进行羟基化，随后进行葡萄糖醛酸化，以及O-去甲基化，随后进行葡萄糖醛酸化或硫酸化；对于THC，THC葡萄糖醛酸化、11-羟基化，随后进行羧化和葡萄糖醛酸化。与THC不同，在尿液中未检测到两种SCs的母体化合物。这些结果与从人肝细胞和/或人体病例研究中获得的结果一致。JWH-210摄入的尿液标志物是N-羟基戊基代谢物的葡萄糖醛酸苷（可检测3-4小时），而RCS-4的尿液标志物是N-羟基戊基、羟基甲氧基苯基的葡萄糖醛酸苷（至少可检测6小时）以及O-去甲基羟基代谢物（可检测4小时）。版权所有© 2016 John Wiley & Sons, Ltd.
