Simultaneous determination of gefitinib and its major metabolites in mouse plasma by HPLC-MS/MS and its application to a pharmacokinetics study.
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.
['Zheng|Nan|N|', 'Zhao|Can|C|', 'He|Xi-Ran|XR|', 'Jiang|Shan-Tong|ST|', 'Han|Shu-Yan|SY|', 'Xu|Guo-Bing|GB|', 'Li|Ping-Ping|PP|']
D000818:Animals D002851:Chromatography, High Pressure Liquid D004355:Drug Stability D005260:Female D000077156:Gefitinib D016014:Linear Models D051379:Mice D008819:Mice, Nude D011799:Quinazolines D015203:Reproducibility of Results D012680:Sensitivity and Specificity D053719:Tandem Mass Spectrometry
Gefitinib Metabolites Mouse plasma Pharmacokinetics LC–MS/MS