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Metabolite identification of a new tyrosine kinase inhibitor, HM781-36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry
RATIONALE HM781‐36B (1‐[4‐[4‐(3,4‐dichloro‐2‐fluorophenylamino)‐7‐methoxyquinazolin‐6‐yloxy]‐piperidin‐1‐yl]prop‐2‐en‐1‐one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781‐36B in vitro and in vivo we validated an...
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Published in: | Rapid communications in mass spectrometry 2013-06, Vol.27 (11), p.1183-1195 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | RATIONALE
HM781‐36B (1‐[4‐[4‐(3,4‐dichloro‐2‐fluorophenylamino)‐7‐methoxyquinazolin‐6‐yloxy]‐piperidin‐1‐yl]prop‐2‐en‐1‐one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781‐36B in vitro and in vivo we validated an analytical method for HM781‐36B and its major metabolites in plasma.
METHODS
In vivo and in vitro metabolism of HM781‐36B was studied in dog plasma, urine and feces as well as using human and dog liver microsomes with extraction by ethyl acetate or methyl tert‐butyl ether, respectively, and successfully separated by high‐performance liquid chromatography diode‐array detection mass spectrometry (HPLC‐DAD/MS). Ten metabolites were identified by LC/ESI‐ion trap mass spectrometry (MS, MS2, MS3 and MRM) and LC/Q‐TOF‐MS/MS for exact mass measurement. For accurate characterization of the major metabolites, authentic standards (M1, M2, M4, and M10) were synthesized.
RESULTS
Ten metabolites of HM781‐36B in an in vitro mixture were separated and identified by LC/ESI‐MSn. The MS/MS spectral patterns of the parent drug and metabolites exhibited two characteristic ions (A‐ and B‐type ions) attributed to the cleavage of the ether bond between the piperidine ring and the quinazoline ring, providing important information on the site of chemical conversion during the metabolism. Six hydroxylated derivatives including dehalogenation and demethylation, two N‐oxide forms, a demethylated form and de‐acryloylpiperideine metabolites were observed.
CONCLUSIONS
The LC/ESI‐ion trap MSn technique was effective in obtaining structural information and yielded diagnostic ions for the identification of diverse metabolites. The multiple metabolic pathways of HM781‐36B were suggested in in vitro and in vivo samples and the dihydroxylation (M1) and demethylation (M2) appeared to be the major metabolites. Copyright © 2013 John Wiley & Sons, Ltd. |
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ISSN: | 0951-4198 1097-0231 |
DOI: | 10.1002/rcm.6559 |