Metabolic Activation of Perampanel Mediated by CYP1A2

谷胱甘肽 化学 微粒体 细胞毒性 药理学 CYP1A2 体内 生物化学 细胞色素P450 乙酰半胱氨酸 体外 敌手 结合 受体 生物 抗氧化剂 数学 生物技术 数学分析
作者
Zifang Ding,Xu Wang,Ning Zhang,Chen Sun,Guode Zhao,Ying Peng,Jiang Zheng
出处
期刊:Chemical Research in Toxicology [American Chemical Society]
卷期号:35 (3): 490-498 被引量:4
标识
DOI:10.1021/acs.chemrestox.1c00396
摘要

Perampanel (PRP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist with high selectivity, has been used as a new adjuvant for the treatment of fractional seizures with or without primary generalized tonic-clonic seizures and secondary generalized seizures in epilepsy patients over the age of 12. Adverse events such as liver injury have been reported during the clinical application of PRP. The purpose of the study is to explore the in vitro and in vivo metabolic activation of PRP. Two GSH conjugates were detected in rat liver microsomal incubations containing PRP, GSH, and NADPH. The two GSH conjugates were both obtained from the bile of rats and rat primary hepatocytes after exposure to PRP. Similar microsomal incubations complemented with N-acetylcysteine (NAC) in place of GSH offered two NAC conjugates. As expected, the NAC conjugates were detected in the urine of PRP-treated rats. One of the two NAC conjugates was identified as NAC conjugate 12 verified by chemical synthesis. The individual human recombinant P450 enzyme incubation assay demonstrated that CYP1A2 dominated the catalysis for the metabolic activation of PRP. Pretreatment with α-naphthoflavone (NTF) decreased the formation of PRP-derived GSH conjugates in both livers of rats and cultured primary hepatocytes after being treated with PRP. Additionally, NTF was found to decrease the susceptibility of primary hepatocytes to the cytotoxicity of PRP. The findings indicate that PRP was metabolized to the corresponding epoxide, which could participate in PRP-induced cytotoxicity.
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