Institute of Legal Medicine, Saarland University, 66421 Homburg, Germany.
Institute for Clinical and Experimental Surgery, Saarland University, 66421 Homburg, Germany.
Toxicol Lett. 2020 Sep 1;329:12-19. doi: 10.1016/j.toxlet.2020.04.001. Epub 2020 May 4.
Being highly potent, New Synthetic Opioids (NSO) have become a public health concern. Little is known though about the metabolism and toxicokinetics (TK) of many of the non fentanyl NSO such as U-47700. Obtaining such data in humans is challenging and so we investigated if pigs were a suitable model species as TK model for U-47700. The metabolic fate of U-47700 was elucidated after intravenous administration to one pig in vivo and results were compared to metabolic patterns formed by different other in vitro systems (human and pig liver microsomes, human liver S9 fraction) and compared to rat and human in vivo data. Furthermore, monooxygenase isozymes responsible for the major metabolic steps were elucidated. In total, 12 phase I and 8 phase II metabolites of U-47700 could be identified. The predominant reactions were N-demethylation, hydroxylation, and combination of them followed by glucuronidation or sulfation. The most predominant monooxygenase catalyzed conversions were N-demethylation, and hydroxylation by CYP3A4 and 2B6, and FMO3 catalyzed N-oxidation. Similar main phase I metabolites were found in vitro as compared to in vivo (pig/human). The metabolic pattern elucidated in the pig was comparable to human in vivo data. Thus, pigs seem to be a suitable animal model for metabolism and further TK of U-47700.
新型合成阿片类药物（NSO）具有很强的效力，已成为公共卫生关注的焦点。然而，对于许多非芬太尼类的 NSO，如 U-47700，其代谢和毒代动力学（TK）知之甚少。在人体内获得这些数据具有挑战性，因此我们研究了猪是否可以作为 U-47700 的 TK 模型的合适物种模型。在体内静脉给予一头猪后，阐明了 U-47700 的代谢命运，并将结果与不同体外系统（人肝和猪肝微粒体、人肝 S9 级分）形成的代谢模式进行比较，并与大鼠和人体的体内数据进行比较。此外，阐明了负责主要代谢步骤的单加氧酶同工酶。总共可以鉴定出 12 种 U-47700 的 I 相和 8 种 II 相代谢物。主要反应是 N-去甲基化、羟化，随后是葡萄糖醛酸化或硫酸化。最主要的单加氧酶催化转化是 CYP3A4 和 2B6 催化的 N-去甲基化和羟化，以及 FMO3 催化的 N-氧化。与体内（猪/人）相比，在体外发现了相似的主要 I 相代谢物。在猪中阐明的代谢模式与人体的体内数据相当。因此，猪似乎是 U-47700 代谢和进一步 TK 的合适动物模型。
