Pyrotinib is an irreversible EGFR/HER2 inhibitor, which has been approved for the treatment of breast cancer. The aim of this work was to establish a quantification method for simultaneous determination pyrotinib and its metabolite pyrotinib-lactam in rat plasma using ultra-high performance liquid chromatography tandem mass spectrometer (UPLC-MS/MS). After simple protein precipitation with acetonitrile, the analytes and IS (neratinib) were separated on an ACQUITY BEH C column (2.1 × 50 mm, 1.7 μm) using a mobile phase of water containing 0.1% formic acid and acetonitrile. The detection was performed using selected reaction monitoring (SRM) mode with precursor-to-product ion transitions at m/z 583.2 > 138.1 for pyrotinib, m/z 597.2 > 152.1 for pyrotinib-lactam and m/z 557.2 > 112.1 for IS. The assay showed excellent linearity over the concentration range of 0.5-1000 ng/mL for pyrotinib and pyrotinib-lactam. The assay met the criteria of FDA-validated bioanalytical methods and was successfully applied to a pharmacokinetic study of pyrotinib and its metabolite for the first time. Our results demonstrated that pyrotinib was rapidly converted into pyrotinib-lactam, of which the in vivo exposure was 21% of that of pyrotinib.
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