Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients

doi:10.1111/bcp.14621

	Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients
	Liu, Lu 1,2; Wang, Qian 3; Xie, Cen 1,2; Xi, Ning 3; Guo, Zitao 2; Li, Ming 3; Hou, Xiangyu 1,2; Xie, Ningjie 1,2; Sun, Mingming 3; Li, Jing 3
刊名	BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
	2020-11-15
页码	13
关键词	drug– drug interaction gefitinib ningetinib transporters
ISSN号	0306-5251
DOI	10.1111/bcp.14621
通讯作者	Chen, Xiaoyan(xychen@simm.ac.cn)
英文摘要	Aims Ningetinib is a tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC). The present study aims to investigate the drug interaction of ningetinib and gefitinib and the mechanism of high plasma exposure of N-demethylated ningetinib (M1) in NSCLC patients. Methods Patients with NSCLC were recruited. Metabolism and transport assays were performed using in vitro models. Deuterated M1 was used to study the effects of ningetinib and gefitinib on M1 efflux in Institute of Cancer Research (ICR) mice. Results Upon co-administration of ningetinib with gefitinib, the plasma exposure of M1 was reduced by 80%, whereas that of ningetinib was not affected. In vitro experiments indicated that CYP1A1 was primarily responsible for M1 formation. Gefitinib was demonstrated to be a strong inhibitor of CYP1A1 with K-i value of 0.095 mu M. M1 was identified as a substrate of efflux transporters P-gp and BCRP, while ningetinib and gefitinib were demonstrated to be their inhibitors, which was consistent with the results in mice. However, the inhibitory effect of gefitinib on efflux in vivo was negligible in the presence of ningetinib. Conclusion The high plasma exposure of M1 in patients was attributed to the inhibition of M1 efflux by ningetinib and its low tissue affinity. When co-administered, gefitinib inhibited the formation of M1, but due to the low metabolic yield of M1 in vivo, the pharmacokinetics of ningetinib was not influenced. Inhibition of CYP1A1 may increase the concentration of ningetinib in target tissues, and the long-term safety and efficacy of ningetinib combined with gefitinib should be evaluated.
资助项目	Guangdong Innovative and Entrepreneurial Research Team Program[2016ZT06Y616] ; Strategic Priority Research Program of the Chinese Academy of Science[12050306] ; General Program of National Natural Science Foundation of China[82073924]
WOS关键词	RESISTANCE ; EXPRESSION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000589174600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292599]
专题	中国科学院上海药物研究所
通讯作者	Chen, Xiaoyan
作者单位	1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Sunshine Lake Pharma Co Ltd, State Key Lab Antiinfect Drug Dev 2015DQ780357, Dongguan 523871, Peoples R China
推荐引用方式 GB/T 7714	Liu, Lu,Wang, Qian,Xie, Cen,et al. Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients[J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY,2020:13.
APA	Liu, Lu.,Wang, Qian.,Xie, Cen.,Xi, Ning.,Guo, Zitao.,...&Chen, Xiaoyan.(2020).Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients.BRITISH JOURNAL OF CLINICAL PHARMACOLOGY,13.
MLA	Liu, Lu,et al."Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients".BRITISH JOURNAL OF CLINICAL PHARMACOLOGY (2020):13.