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Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum AlbuminS

文献类型：期刊论文

作者Wu, Yali4,5; Chen, Lili4,5; Chen, Jian1,3; Xue, Hao5; He, Qingfeng2; Zhong, Dafang4,5; Diao, Xingxing4,5
刊名DRUG METABOLISM AND DISPOSITION
出版日期2023
卷号51期号:1页码:8-16
DOI10.1124/dmd.122.001019
文献子类Article
英文摘要As third-generation tyrosine kinase inhibitors, furmonertinib and osimertinib exhibit better efficacy than first-and second-generation tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. However, radioactive pharmacokinetics studies showed that parent-related components remain in human plasma for at least 21 days after oral administration. Similar pharmacokinetic profiles were found in pyrotinib and neratinib, which have been identified to covalently bind with human serum albumin at Lys-190, leading to low extraction recovery in protein precipitation. However, the binding mechanism of furmonertinib and osimertinib in human plasma has not been confirmed. Comprehensive techniques were used to investi-gate the mechanism of this binding, including ultra high-performance liquid chromatography coupled with high-resolution mass spectrom-etry and online/offline radioactivity profiling. SDS-PAGE and further autoradiography were also used to detect drug-protein adducts. We found that most furmonertinib exists in the human plasma following ex vivo incubation in the form of protein-drug adducts. Only lysine-furmonertinb adducts were found in pronase digests. A standard ref-erence of lysine-furmonertinib was synthesized and confirmed by NMR. Through peptide mapping analysis, we confirmed that furmo-nertinib almost exclusively binds with human serum albumin (HSA) in plasma following ex vivo incubation, via Michael addition at Lys-195 and Lys-199, instead of Lys-190. Two peptides found to bond with fur-monertinib were ASSAKQR and LKCASLQK. Osimertinib was also found to bond with Lys-195 and Lys-199 of HSA via peptide mapping analysis. SIGNIFICANCE STATEMENT Here we report that furmonertinib and osimertinib can covalently bind with human serum albumin at the site of Lys-195 and Lys-199 instead of Lys-190, potentially leading to the long duration of drug -protein adducts in the human body.
WOS关键词HAPTENIC STRUCTURES
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000928418800002
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/309725]  
专题新药研究国家重点实验室
通讯作者Zhong, Dafang; Diao, Xingxing
作者单位1.Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Shanghai, Peoples R China
2.Fudan Univ, Sch Pharm, Dept Clin Pharm & Pharm Adm, Shanghai, Peoples R China;
3.Fudan Univ, Sch Pharm, Radiopharm & Mol Imaging Ctr, Shanghai, Peoples R China;
4.Univ Chinese Acad Sci, Beijing, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Wu, Yali,Chen, Lili,Chen, Jian,et al. Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum AlbuminS[J]. DRUG METABOLISM AND DISPOSITION,2023,51(1):8-16.
APA Wu, Yali.,Chen, Lili.,Chen, Jian.,Xue, Hao.,He, Qingfeng.,...&Diao, Xingxing.(2023).Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum AlbuminS.DRUG METABOLISM AND DISPOSITION,51(1),8-16.
MLA Wu, Yali,et al."Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum AlbuminS".DRUG METABOLISM AND DISPOSITION 51.1(2023):8-16.

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来源：上海药物研究所

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