title: Simultaneous determination of gefitinib and its major metabolites in mouse plasma by HPLC-MS/MS and its application to a pharmacokinetics study.
abstract: Gefitinib (Iressa) is the first oral EGFR tyrosine kinase inhibitor and it brings benefits to non-small cell lung cancer patients with EGFR mutation. In this study, a simple, rapid and credible high performance liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous quantification of gefitinib and its main metabolites M523595, M537194, M387783 and M608236 in NSCLC tumor-bearing mouse plasma. Sample extraction was done by protein precipitation using acetonitrile containing dasatinib as the internal standard. The chromatography run time was 6min using an Agilent RRHD SB-C18 column with a gradient of acetonitrile and water (0.1% formic acid, v/v). The mass analysis was performed by a triple quadrupole mass spectrometry in positive multiple reaction monitoring mode. The calibration range was 0.5-100ng/mL for M608236 and 1-200ng/mL for other analytes with the correlation coefficients (r(2))≥0.99. For quality control samples, inter- and intra-assay precision was less than 15% and accuracies ranged from 92.6% to 107.58% for all analytes. The extraction recoveries were in the range of 86-105% and no significant matrix effect was observed. This simple and reproducible high-throughput method was successfully applied to the pharmacokinetic study of gefitinib and its major metabolites in mouse.
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; National Drug Clinical Trial Center, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Can
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Xi-Ran
authors.initials: XR
authors.lastname: He
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Shan-Tong
authors.initials: ST
authors.lastname: Jiang
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China. Electronic address: shuyanhan@bjmu.edu.cn.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Han
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; National Drug Clinical Trial Center, Peking University Cancer Hospital & Institute, Beijing 100142, PR China.
authors.forename: Guo-Bing
authors.initials: GB
authors.lastname: Xu
authors.affiliation: Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, PR China; Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China. Electronic address: lppma123@sina.com.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Li
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D005260:Female; D000077156:Gefitinib; D016014:Linear Models; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D011799:Quinazolines; D000077156:Gefitinib
keywords: Gefitinib; LC–MS/MS; Metabolites; Mouse plasma; Pharmacokinetics