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Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2018-02-15 , DOI: 10.1002/dta.2355 Sascha K Manier 1 , Lilian H J Richter 1 , Jan Schäper 2 , Hans H Maurer 1 , Markus R Meyer 1
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2018-02-15 , DOI: 10.1002/dta.2355 Sascha K Manier 1 , Lilian H J Richter 1 , Jan Schäper 2 , Hans H Maurer 1 , Markus R Meyer 1
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In vitro and in vivo experiments are widely used for studying the metabolism of new psychoactive substances (NPS). The availability of such data is required for toxicological risk assessments and development of urine screening approaches. This study investigated the in vitro metabolism of the 5 pyrrolidinophenone‐derived NPS alpha‐pyrrolidinobutyrophenone (alpha‐PBP), alpha‐pyrrolidinopentiothiophenone (alpha‐PVT), alpha‐pyrrolidinohexanophenone (alpha‐PHP), alpha‐pyrrolidinoenanthophenone (alpha‐PEP, PV8), and alpha‐pyrrolidinooctanophenone (alpha‐POP, PV9). First, they were incubated with pooled human liver microsomes (pHLM) or pooled human liver S9 fraction (pS9) for identification of the main phase I and II metabolites. All substances formed hydroxy metabolites and lactams. Longer alkyl chains resulted in keto group and carboxylic acid formation. Comparing these results with published data obtained using pHLM, primary human hepatocytes (PHH), and authentic human urine samples, PHH provided the most extensive metabolism. Second, enzyme kinetic studies showed that the initial metabolic steps were formed by cytochrome P450 isoforms (CYP) CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 resulting in pyrrolidine, thiophene or alkyl hydroxy metabolites depending on the length of the alkyl chain. The kinetic parameters indicated an increasing affinity of the CYP enzymes with increase of the length of the alkyl chain. These parameters were then used to calculate the contribution of a single CYP enzyme to the in vivo hepatic clearance. CYP2C19 and CYP2D6 were mainly involved in the case of alpha‐PBP and CYP1A2, CYP2C9 and CYP2C19 in the case of alpha‐PVT, alpha‐PHP, alpha‐PEP, and alpha‐POP.
中文翻译：
用于阐明 α-卡西酮衍生药物滥用的人体代谢的不同体外和体内工具
体外和体内实验广泛用于研究新型精神活性物质（NPS）的代谢。毒理学风险评估和尿液筛查方法的开发需要此类数据的可用性。本研究研究了 5 种吡咯烷苯衍生的 NPS α-吡咯烷丁苯酮 (α-PBP)、α-吡咯烷五噻吩酮 (α-PVT)、α-吡咯烷己苯酮 (α-PHP)、α-吡咯烷二苯并苯酮 (α-PEP、PV8) 的体外代谢）和α-吡咯烷辛苯酮（α-POP，PV9）。首先，将它们与混合的人肝微粒体 (pHLM) 或混合的人肝 S9 组分 (pS9) 一起孵育，以鉴定主要的 I 期和 II 期代谢物。所有物质均形成羟基代谢物和内酰胺。较长的烷基链导致酮基和羧酸的形成。将这些结果与使用 pHLM、原代人肝细胞 (PHH) 和真实的人尿液样本获得的已发表数据进行比较，PHH 提供了最广泛的代谢。其次，酶动力学研究表明，最初的代谢步骤是由细胞色素 P450 同工型 (CYP) CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4 形成，根据烷基链的长度产生吡咯烷、噻吩或烷基羟基代谢物。动力学参数表明CYP酶的亲和力随着烷基链长度的增加而增加。然后使用这些参数来计算单个 CYP 酶对体内肝脏清除率的贡献。 CYP2C19和CYP2D6主要涉及α-PBP，CYP1A2、CYP2C9和CYP2C19主要涉及α-PVT、α-PHP、α-PEP和α-POP。
更新日期：2018-02-15
中文翻译：
用于阐明 α-卡西酮衍生药物滥用的人体代谢的不同体外和体内工具
体外和体内实验广泛用于研究新型精神活性物质（NPS）的代谢。毒理学风险评估和尿液筛查方法的开发需要此类数据的可用性。本研究研究了 5 种吡咯烷苯衍生的 NPS α-吡咯烷丁苯酮 (α-PBP)、α-吡咯烷五噻吩酮 (α-PVT)、α-吡咯烷己苯酮 (α-PHP)、α-吡咯烷二苯并苯酮 (α-PEP、PV8) 的体外代谢）和α-吡咯烷辛苯酮（α-POP，PV9）。首先，将它们与混合的人肝微粒体 (pHLM) 或混合的人肝 S9 组分 (pS9) 一起孵育，以鉴定主要的 I 期和 II 期代谢物。所有物质均形成羟基代谢物和内酰胺。较长的烷基链导致酮基和羧酸的形成。将这些结果与使用 pHLM、原代人肝细胞 (PHH) 和真实的人尿液样本获得的已发表数据进行比较，PHH 提供了最广泛的代谢。其次，酶动力学研究表明，最初的代谢步骤是由细胞色素 P450 同工型 (CYP) CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4 形成，根据烷基链的长度产生吡咯烷、噻吩或烷基羟基代谢物。动力学参数表明CYP酶的亲和力随着烷基链长度的增加而增加。然后使用这些参数来计算单个 CYP 酶对体内肝脏清除率的贡献。 CYP2C19和CYP2D6主要涉及α-PBP，CYP1A2、CYP2C9和CYP2C19主要涉及α-PVT、α-PHP、α-PEP和α-POP。
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