Schaefer Nadine, Wojtyniak Jan-Georg, Kettner Mattias, Schlote Julia, Laschke Matthias W, Ewald Andreas H, Lehr Thorsten, Menger Michael D, Maurer Hans H, Schmidt Peter H
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany.
Clinical Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
Toxicol Lett. 2016 Jun 24;253:7-16. doi: 10.1016/j.toxlet.2016.04.021. Epub 2016 Apr 23.
Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs.
合成大麻素（SCs）在临床和法医毒理学中的重要性日益增加。它们在没有任何临床前安全性研究的情况下被使用。因此，尽管在药物滥用或中毒案件中对分析结果的解释具有相关性，但不允许进行对照人体药代动力学（PK）研究。作为替代方法，在一项对照动物实验中，每种药物的六头猪分别接受了200μg/kg体重的单次静脉注射剂量的Δ(9)-四氢大麻酚（THC）、4-乙基萘-1-基-(1-戊基吲哚-3-基)甲酮（JWH-210）或2-(4-甲氧基苯基)-1-(1-戊基吲哚-3-基)甲酮（RCS-4）。此外，六头猪接受了三种药物相同剂量的组合。使用液相色谱-串联质谱法（LC-MS/MS）测定血清中的药物。群体（pop）PK分析表明，三室模型最能描述所有三种大麻素的PK数据。THC、JWH-210和RCS-4的中央分布容积分别估计为0.29L/kg、0.20L/kg和0.67L/kg。THC、JWH-210和RCS-4的清除率分别为0.042L/分钟/千克、0.048L/分钟/千克和0.093L/分钟/千克。使用异速生长技术将popPK THC猪模型按比例放大到人类。与已发表的人类数据比较表明，可以成功预测浓度-时间曲线。这些发现表明，猪结合PK建模技术可作为预测SCs人体PK的工具。
