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 |
ISSN | 0340-5761 |
EISSN | 1432-0738 |
卷号 | 97期号:8页码:2133-2142 |
DOI | 10.1007/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 ID | 37209178 |
SCOPUSEID | 2-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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