Abstract | BACKGROUND: MATERIALS AND METHODS: An ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry (UPLCQ-TOF-MS) method was established to tentatively identify the metabolites of gefitinib in human plasma. The extracted ion chromatogram peak intensity threshold was set at 1500 cps with minimum MS and MS/MS peak intensities of 400 and 100 cps, respectively. RESULTS: A total of 18 tentative metabolites were identified. Eight novel tentative metabolites with metabolic changes in dechlorination, defluorination, and hydrogenation on the quinazoline skeleton; removal of a partial or complete 3-chloro-4-fluoroaniline-substituted group; and sulfate conjugation and taurine conjugation were newly discovered in human plasma. Based on structural analysis of the tentative metabolites, the metabolic pathways were proposed. In addition, the pathways of dechlorination, defluorination, and hydrogenation on the quinazoline skeleton; removal of partial or complete 3-chloro-4-fluoroaniline-substituted groups; and sulfate conjugation and taurine conjugation in humans in vivo indicate that novel metabolic pathways exist in humans. CONCLUSIONS: In summary, the metabolism of gefitinib in humans in vivo is extensive and complex. Based on in vivo evidence, the propoxy- morpholine ring side chain and O-methyl group are the critical metabolic regions of gefitinib in humans. The novel metabolic pathways differ from those of in vitro studies, suggesting that intestinal floral metabolism might be involved.
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Authors | Chao Wang, Jingui Zhang, Simin Zhou, Limei Yu, Fangxuan Han, Ren Ling, Jin Ling |
Journal | PloS one
(PLoS One)
Vol. 15
Issue 7
Pg. e0236523
( 2020)
ISSN: 1932-6203 [Electronic] United States |
PMID | 32702075
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Carcinoma, Non-Small-Cell Lung
(blood, drug therapy)
- Chromatography, High Pressure Liquid
- Gefitinib
(blood, chemistry, metabolism, therapeutic use)
- Humans
- Lung Neoplasms
(blood, drug therapy)
- Male
- Middle Aged
- Tandem Mass Spectrometry
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