Due to the dynamic market involving synthetic cannabinoids (SCs), the determination of analytical targets is challenging in clinical and forensic toxicology. SCs usually undergo extensive metabolism, and therefore their main metabolites must be identified for the detection in biological matrices, particularly in urine. Controlled human studies are usually not possible for ethical reasons; thus, alternative models must be used. The aim of this work was to predict the in vitro and in vivo metabolic patterns of 7‐azaindole‐derived SCs using 1‐(5‐fluoropentyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H‐pyrollo[2,3‐b]pyridin‐3‐carboxamide (cumyl‐5F‐P7AICA) as an example. Different in vitro (pooled human liver S9 fraction, pooled human liver microsomes, and pig liver microsomes) and in vivo (rat and pig) systems were compared. Monooxygenase isoenzymes responsible for the most abundant phase I steps, namely oxidative defluorination (OF) followed by carboxylation, monohydroxylation, and ketone formation, were identified. In both in vivo models, OF/carboxylation and N‐dealkylation/monohydroxylation/sulfation could be detected. Regarding pHS9 and pig urine, monohydroxylation/sulfation or glucuronidation was also abundant. Furthermore, the parent compound could still be detected in all models. Initial monooxygenase activity screening revealed the involvement of CYP2C19, CYP3A4, and CYP3A5. Therefore, in addition to the parent compound, the OF/carboxylated and monohydroxylated (and sulfated or glucuronidated) metabolites can be recommended as urinary targets. In comparison to literature, the pig model predicts best the human metabolic pattern of cumyl‐5F‐P7AICA. Furthermore, the pig model should be suitable to mirror the time‐dependent excretion pattern of parent compounds and metabolites.

中文翻译：

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用于阐明 7-氮杂吲哚衍生的合成大麻素代谢模式的体外和体内模型的比较，以 cumyl-5F-P7AICA 为例。

由于涉及合成大麻素 (SC) 的动态市场，分析目标的确定在临床和法医毒理学中具有挑战性。SCs 通常经历广泛的代谢，因此必须确定它们的主要代谢物，以便在生物基质中进行检测，特别是在尿液中。出于伦理原因，受控的人体研究通常是不可能的；因此，必须使用替代模型。这项工作的目的是使用 1-(5-氟戊基) -N- (2-苯基丙-2-基)-1 H-吡咯[2]预测7-氮杂吲哚衍生的 SCs 的体外和体内代谢模式。, 3- b ]吡啶-3-甲酰胺（枯基-5F-P7AICA）为例。体外不同（合并的人肝 S9 级分、合并的人肝微粒体和猪肝微粒体）和体内（大鼠和猪）系统进行了比较。确定了负责最丰富的 I 阶段步骤的单加氧酶同工酶，即氧化脱氟 (OF)，然后是羧化、单羟基化和酮形成。在两种体内模型中，OF/羧化和N可以检测到脱烷基化/单羟基化/硫酸化。关于 pHS9 和猪尿，单羟基化/硫酸化或葡萄糖醛酸化也很丰富。此外，在所有模型中仍可检测到母体化合物。最初的单加氧酶活性筛选揭示了 CYP2C19、CYP3A4 和 CYP3A5 的参与。因此，除母体化合物外，还可推荐 OF/羧化和单羟基化（以及硫酸化或葡萄糖醛酸化）代谢物作为尿液目标。与文献相比，猪模型最能预测 cumyl-5F-P7AICA 的人类代谢模式。此外，猪模型应该适合反映母体化合物和代谢物的时间依赖性排泄模式。