Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany.
State Bureau of Criminal Investigation Schleswig-Holstein, 24116 Kiel, Germany.
J Anal Toxicol. 2020 Apr 2;44(5):449-460. doi: 10.1093/jat/bkaa010.
The growing number of new synthetic opioids (NSO) on the new psychoactive substances (NPS) market bears new challenges in toxicology. As their toxicodynamics and particularly their toxicokinetics are usually unknown, impact on human health is not yet fully understood. Detection of the 2 NSO cyclopentanoyl-fentanyl (CP-F) and tetrahydrofuranoyl-fentanyl (THF-F) was first reported in 2016. Both were involved in several fatal intoxication cases, but no detailed information about their toxicological characteristics is available so far. The main purpose of this study was therefore to investigate the in vitro toxicokinetics and in vivo analytical toxicology of CP-F and THF-F by means of liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). These studies included metabolic stability, phase I and II metabolism, isozyme mapping, plasma protein binding and detectability in LC-HRMS/MS standard urine screening approaches (SUSA) using rat urine samples. In total, 12 phase I metabolites of CP-F and 13 of THF-F were identified, among them 9 metabolites described for the first time. Overall, N-dealkylations, hydroxylations and dihydroxylations were the main metabolic reactions. The cytochrome P450 (CYP) isozymes mainly involved were CYP2D6 and CYP3A4, leading to elevated drug levels and intoxications in CYP2D6 poor metabolizers. CP-F showed a high plasma protein binding of 99%, which may increase the risk of toxicity by simultaneous intake of other highly bound drugs. Detectability studies showed that neither the parent compounds nor their metabolites were detectable in rat urine using LC-HRMS/MS SUSA. However, a more sophisticated analytical strategy was successfully applied and should be used for analytical confirmation of an intake of CP-F and/or THF-F.
新精神活性物质（NPS）市场中新合成阿片类物质（NSO）的数量不断增加，给毒理学带来了新的挑战。由于其毒代动力学，特别是毒代动力学通常未知，因此对人类健康的影响尚不完全清楚。2016 年首次报道了 2 种 NSO 环戊基芬太尼（CP-F）和四氢呋喃基芬太尼（THF-F）的检测。两者都涉及到几起致命的中毒案例，但迄今为止，还没有关于其毒理学特征的详细信息。因此，本研究的主要目的是通过液相色谱高分辨串联质谱（LC-HRMS/MS）研究 CP-F 和 THF-F 的体外毒代动力学和体内分析毒理学。这些研究包括代谢稳定性、I 相和 II 相代谢、同工酶图谱、血浆蛋白结合和 LC-HRMS/MS 标准尿液筛选方法（SUSA）中的检测性，使用大鼠尿液样本。总共鉴定出 CP-F 的 12 种 I 相代谢物和 THF-F 的 13 种代谢物，其中 9 种代谢物为首次描述。总体而言，N-脱烷基化、羟基化和二羟基化是主要的代谢反应。主要涉及的细胞色素 P450（CYP）同工酶为 CYP2D6 和 CYP3A4，导致 CYP2D6 代谢不良者药物水平升高和中毒。CP-F 的血浆蛋白结合率高达 99%，这可能会增加同时摄入其他高结合药物的毒性风险。检测性研究表明，使用 LC-HRMS/MS SUSA 无法在大鼠尿液中检测到母体化合物及其代谢物。然而，成功应用了更复杂的分析策略，应将其用于 CP-F 和/或 THF-F 摄入的分析确认。
