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Quantification of the major circulating metabolite of BS1801, an ebselen analog, in human plasma

文献类型：期刊论文

作者Tian, Qianqian2,3; Jiang, Jinfang1; Yin, Hanwei4; Ma, Jiao1; Deng, Guozhen1; Zhou, Jialan2; Zhong, Dafang2,3
刊名JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
出版日期2022-04-01
卷号212页码:10
ISSN号0731-7085
关键词BS1801 Ebselen Circulating metabolite Human plasma LC-MS/MS
DOI10.1016/j.jpba.2022.114638
通讯作者Zhong, Dafang(dfzhong@simm.ac.cn)
英文摘要BS1801 contains two selenium atoms in its structure, which is a specific inhibitor of thioredoxin reductase intended to treat fibrotic interstitial pneumonia (control pulmonary fibrosis) and liver fibrosis. It is currently in phase I clinical trial. However, there was no report about the metabolic transformation and pharmacokinetics of BS1801. In this study, BS1801 metabolites were characterized in the hepatocytes of different species (monkey, dog, mouse, rat, and human) and plasma specimens using the ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC/Q-TOF MS) method. After incubation, BS1801 could not be detected in the hepatocytes of different species and human plasma. Five metabolites were identified based on the characteristic peak clusters of selenium atoms in the mass spectrum, combined with the product ions obtained by MS-MS through collision-induced-dissociation (CID), including M1 (reduction metabolite), M2 (reduction and Se-methylation metabolite), M4 (M2 further oxidized metabolite) and M5 (Se-methylation and Se-glucuronidation conjugation metabolite), of which the amount of M2 was the highest. By comparing the LC-MS information with the synthesized reference substance, the structure of M2 was confirmed. The principal BS1801 metabolic pathways were identified as reduction and Se-methylation in humans. Subsequently, an accurate and fast LC-MS/MS method was established to verify the major metabolite M2 in human plasma. Acetonitrile-induced protein precipitation was employed to extract M2 from human plasma. The metabolite was separated through XDB-C-18 (4.6 x 50 mm, 1.8 mu m) under isocratic elution with ammonium acetate (5 mM) containing 0.1% formic acid solution (A) and acetonitrile (B) as the mobile phases. A deuterated internal standard for M2 was prepared to overcome the influence of matrix effects during the detection. The bioanalytical method was shown to be precise, specific, accurate, and good linearity over the range of 3.00-3000 ng/mL, and was implemented to assess the pharmacokinetic profiles of M2 in healthy volunteers following a single oral administration of 450 mg BS1801. This is the first-ever study to identify and quantify the major circulating metabolite of ebselen analogs in human plasma.
WOS关键词ACTIVE SELENOORGANIC COMPOUND ; BIOTRANSFORMATION
资助项目National Natural Science Foundation of China[81521005]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者ELSEVIER
WOS记录号WOS:000763593000001
源URL[http://119.78.100.183/handle/2S10ELR8/300194]  
专题新药研究国家重点实验室
通讯作者Zhong, Dafang
作者单位1.HQ Biosci Co Ltd, Suzhou 215123, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201210, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Shanghai Yuanxi Med Corp, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Tian, Qianqian,Jiang, Jinfang,Yin, Hanwei,et al. Quantification of the major circulating metabolite of BS1801, an ebselen analog, in human plasma[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2022,212:10.
APA Tian, Qianqian.,Jiang, Jinfang.,Yin, Hanwei.,Ma, Jiao.,Deng, Guozhen.,...&Zhong, Dafang.(2022).Quantification of the major circulating metabolite of BS1801, an ebselen analog, in human plasma.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,212,10.
MLA Tian, Qianqian,et al."Quantification of the major circulating metabolite of BS1801, an ebselen analog, in human plasma".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 212(2022):10.

入库方式： OAI收割

来源：上海药物研究所

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