New psychoactive substances (NPS), especially synthetic cannabinoids (SC) remain a public health concern. Due to ethical reasons, systematic controlled human studies to elucidate their toxicodynamics and/or toxicokinetics are usually not possible. However, such knowledge is necessary, for example, for determination of screening targets and interpretation of clinical and forensic toxicological data. In the present study, the feasibility of the pig model as an alternative for human in vivo metabolism studies of SC was investigated. For this purpose, the metabolic pattern of the SC methyl-2-{[1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]amino}-3,3-dimethylbutanoate (5F-MDMB-P7AICA) was elucidated in pig urine following inhalative administration (dosage: 200 µg/kg of body weight). The results were compared with human and pig liver microsomal assays and literature. In addition, different incubations with isolated cytochrome-P450 (CYP) monooxygenases were conducted to identify the involved isozymes. In total, nine phase I and three phase II metabolites were identified in pig urine. The most abundant reactions were ester hydrolysis, ester hydrolysis combined with glucuronidation and ester hydrolysis combined with hydroxylation at the tert-butyl moiety. The parent compound was only found up to 1 h after administration in pig urine. The metabolite formed after hydroxylation and glucuronidation was detectable for 2 h, the one formed after ester hydrolyzation and defluorination for 4 h after administration. All other metabolites were detected during the whole sampling time. The most abundant metabolites were also detected using both microsomal incubations and monooxygenase screenings revealed that CYP3A4 catalyzed most reactions. Finally, pig data showed to be in line with published human data. To conclude, the main metabolites recommended in previous studies as urinary targets were confirmed by using pig urine. The used pig model seems therefore to be a suitable alternative for in vivo metabolism studies of 7-azaindole-derived SC.

中文翻译：

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最近开发的猪模型能否用于 7-氮杂吲哚衍生的合成大麻素的体内代谢研究？使用 5F-MDMB-P7AICA 的研究

新的精神活性物质 (NPS)，尤其是合成大麻素 (SC) 仍然是一个公共卫生问题。由于伦理原因，通常不可能进行系统的受控人体研究来阐明其毒理学和/或毒理学。然而，这些知识是必要的，例如，确定筛选目标以及解释临床和法医毒理学数据。在本研究中，研究了猪模型作为人类 SC 体内代谢研究的替代方案的可行性。为此，SC 甲基-2-{[1-(5-氟戊基)-1 H-吡咯并[2,3- b]的代谢模式]吡啶-3-羰基]氨基}-3,3-二甲基丁酸酯（5F-MDMB-P7AICA）在吸入给药后在猪尿中被阐明（剂量：200微克/公斤体重）。将结果与人和猪肝微粒体测定和文献进行比较。此外，还进行了与分离的细胞色素-P450 (CYP) 单加氧酶的不同孵育以鉴定所涉及的同工酶。总共在猪尿中鉴定出九种 I 期和三种 II 期代谢物。最丰富的反应是酯水解、酯水解与葡萄糖醛酸化结合以及酯水解与叔丁基部分的羟基化结合。在猪尿中给药后最多 1 小时才发现母体化合物。羟基化和葡萄糖醛酸化后形成的代谢物在 2 小时内可检测到，给药后酯水解脱氟4小时形成的。在整个采样时间内检测到所有其他代谢物。使用微粒体孵育和单加氧酶筛选也检测到最丰富的代谢物，表明 CYP3A4 催化了大多数反应。最后，猪数据显示与公布的人类数据一致。总而言之，之前研究中推荐作为尿液目标的主要代谢物已通过使用猪尿得到证实。因此，使用的猪模型似乎是 7-氮杂吲哚衍生 SC 的体内代谢研究的合适替代品。使用微粒体孵育和单加氧酶筛选也检测到最丰富的代谢物，表明 CYP3A4 催化了大多数反应。最后，猪数据显示与公布的人类数据一致。总而言之，之前研究中推荐作为尿液目标的主要代谢物已通过使用猪尿得到证实。因此，使用的猪模型似乎是 7-氮杂吲哚衍生 SC 的体内代谢研究的合适替代品。使用微粒体孵育和单加氧酶筛选也检测到最丰富的代谢物，表明 CYP3A4 催化了大多数反应。最后，猪数据显示与公布的人类数据一致。总而言之，之前研究中推荐作为尿液目标的主要代谢物已通过使用猪尿得到证实。因此，使用的猪模型似乎是 7-氮杂吲哚衍生 SC 的体内代谢研究的合适替代品。