科研成果详情

题名Effects of drug-drug interactions and CYP3A4 variants on alectinib metabolism
作者
发表日期2023-08
发表期刊ARCHIVES OF TOXICOLOGY   影响因子和分区
语种英语
原始文献类型Article ; Early Access
关键词ALK-TKI Alectinib Nicardipine Incubation system
其他关键词SELECTIVE ALK INHIBITOR ; KINASE INHIBITORS ; NICARDIPINE ; CRIZOTINIB ; CH5424802
摘要

In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC50) value of 3.54 +/- 0.96 mu M in RLM and 1.52 +/- 0.038 mu M in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague-Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC((0-t)), AUC((0-infinity)), T-max and C-max of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future.

资助项目National Natural Science Foundation of China[82104297] ; National Key Research and Development Program of China[2020YFC2008301]
出版者SPRINGER HEIDELBERG
ISSN0340-5761
EISSN1432-0738
卷号97期号:8页码:2133-2142
DOI10.1007/s00204-023-03524-1
页数10
WOS类目Toxicology
WOS研究方向Toxicology
WOS记录号WOS:000991190600002
收录类别SCIE ; PUBMED ; SCOPUS
在线发表日期2023-05
URL查看原文
PubMed ID37209178
SCOPUSEID2-s2.0-85160266257
通讯作者地址[Lin, Guanyang]The First Affiliated Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,China ; [Xu, Ren-ai]The First Affiliated Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,China ; [Cai, Jian-ping]The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing,China
Scopus学科分类Toxicology;Health, Toxicology and Mutagenesis
引用统计
文献类型期刊论文
条目标识符https://kms.wmu.edu.cn/handle/3ETUA0LF/180097
专题附属第一医院
药学院(分析测试中心)
通讯作者Cai, Jian-ping; Lin, Guanyang; Xu, Ren-ai
作者单位
1.The First Affiliated Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,China;
2.School of Pharmaceutical Sciences,Wenzhou Medical University,Zhejiang,Wenzhou,China;
3.The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing,China
第一作者单位附属第一医院;  第一临床医学院(信息与工程学院)、附属第一医院
通讯作者单位附属第一医院;  第一临床医学院(信息与工程学院)、附属第一医院
第一作者的第一单位附属第一医院
推荐引用方式
GB/T 7714
Liu, Ya-nan,Chen, Jie,Wang, Jing,et al. Effects of drug-drug interactions and CYP3A4 variants on alectinib metabolism[J]. ARCHIVES OF TOXICOLOGY,2023,97(8):2133-2142.
APA Liu, Ya-nan., Chen, Jie., Wang, Jing., Li, Qingqing., Hu, Guo-xin., ... & Xu, Ren-ai. (2023). Effects of drug-drug interactions and CYP3A4 variants on alectinib metabolism. ARCHIVES OF TOXICOLOGY, 97(8), 2133-2142.
MLA Liu, Ya-nan,et al."Effects of drug-drug interactions and CYP3A4 variants on alectinib metabolism".ARCHIVES OF TOXICOLOGY 97.8(2023):2133-2142.

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