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首页> 外文期刊>Journal of mass spectrometry: JMS >In vitro metabolic fate of alizapride: evidence for the formation of reactive metabolites based on liquid chromatography-tandem mass spectrometry
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In vitro metabolic fate of alizapride: evidence for the formation of reactive metabolites based on liquid chromatography-tandem mass spectrometry

机译：茜素的体外代谢命运：基于液相色谱-串联质谱的反应性代谢物形成证据

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摘要

The study of the formation of reactive metabolites during drug metabolism is one of the major areas of research in drug development since the link between reactive metabolites and drug adverse effects was well recognized. In particular, it has been shown that acrolein, a reactive carbonyl species sharing carbonylating and alkylating properties, binds covalently to nucleophilic sites in proteins, causing cellular damage. Alizapride, (—)-6-methoxy-N-{[1-(prop-2-en-1-yl)-pyrrolidin-2-yl] methyl}-1H-benzotriazole-5-carboxamide, is a N-allyl containing dopamine antagonist with antiemetic properties for which no data concerning its metabolic fate are so far reported. The study of the in vitro metabolism of alizapride showed the formation of acrolein during the oxidative N-deallylation. Moreover, the formation of an epoxide metabolite has been also described suggesting its role as a putative structural alert. The reactivity of the acrolein and the epoxide generated in alizapride metabolism was demonstrated by the formation of the corresponding adducts with nucleophilic thiols. Overall, ten metabolites have been identified and characterized by electrospray ionization tandem mass spectrometry analysis allowing to propose an in vitro metabolic scheme for alizapride. At the best of our knowledge, this is the second case of a drug involved in the generation of acrolein during its metabolism being the first represented by cyclophosphamide.
机译：药物代谢过程中反应性代谢物形成的研究是药物开发的主要研究领域之一，因为反应性代谢物与药物不良反应之间的联系已得到公认。特别地，已经显示出丙烯醛，一种具有羰基化和烷基化性质的反应性羰基物质，与蛋白质中的亲核位点共价结合，从而引起细胞损伤。 Alizapride（-）-6-甲氧基-N-{[1-（prop-2-en-1-yl）-吡咯烷-2-基]甲基} -1H-苯并三唑-5-羧酰胺是N-烯丙基含有具有止吐作用的多巴胺拮抗剂，至今尚未报道有关其代谢命运的数据。茜素的体外代谢研究表明，在氧化N-去烯丙基化过程中形成了丙烯醛。此外，还描述了环氧化物代谢产物的形成，表明其作为假定的结构警报。丙烯醛代谢中产生的丙烯醛和环氧化物的反应性通过与亲核硫醇形成相应的加合物得到证明。总体而言，已经通过电喷雾电离串联质谱分析法鉴定并表征了十种代谢物，从而提出了一种阿利沙必利的体外代谢方案。据我们所知，这是第二种参与新陈代谢过程中丙烯醛生成的药物，它是首个以环磷酰胺为代表的药物。

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