首页 | 本学科首页   官方微博 | 高级检索  
     


Characterization of reactive intermediates formation in dacomitinib metabolism and bioactivation pathways elucidation by LC-MS/MS: in vitro phase I metabolic investigation
Authors:Mohamed   W. Attwa,Adnan A. Kadi,Ali S. Abdelhameed
Affiliation:Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457 Riyadh, 11451 Saudi Arabia, Fax: +966 1146 76 220, +966 1146 70237
Abstract:
Dacomitinib (DCB) is a second generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance developed by the first line epidermal growth factor receptor (EGFR) TKIs. In the current study, metabolites of phase I for DCB were systematically explored. DCB reactive metabolites were also investigated in rat liver microsomes in presence of potassium cyanide or methoxylamine that were employed as capturing agents for iminium reactive intermediates and aldehyde, respectively, to form stable complexes which can be detected by LC-MS/MS. As a result, four in vitro phase I metabolites were observed with major pathway of piperidine ring hydroxylation. Additionally, two potentially reactive intermediates, one aldehyde and one iminium ions were characterized. Two different pathways of bioactivation were ultimately proposed.

Dacomitinib (DCB) is a second generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance developed by the first line epidermal growth factor receptor (EGFR) TKIs.
Keywords:
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号