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Localization of sunitinib, its metabolites and its target receptors in tumor bearing mice: a MALDI mass spectrometry imaging study

Török, Szilvia; Végvári, Ákos LU ; Rezeli, Melinda LU ; Fehniger, Thomas LU ; Tóvári, József; Paku, Sándor; László, Viktória; Hegedüs, Balázs; Rózsás, Anita and Döme, Balázs, et al. (2015) In British Journal of Pharmacology 172(4). p.1148-1163
Abstract
A functional blood vessel network is essential for maintaining the necessary oxygen and nutrient levels in solid tumors. Thus, the inhibition of blood vessel growth by different antiangiogenic agents has become one of the most important topics in cancer research over the past few decades. The in vitro studies of these drugs are promising, but both the in vivo and the clinical experiences are controversial. Therefore, investigating the pharmacokinetic parameters of these compounds is a pivotal issue in drug development. In this study, the detection and the adsorption, distribution, metabolism, elimination (ADME) of the antiangiogenic receptor tyrosine kinase inhibitor (RTKI) sunitinib is analyzed in a subcutaneous syngeneic murine tumor... (More)
A functional blood vessel network is essential for maintaining the necessary oxygen and nutrient levels in solid tumors. Thus, the inhibition of blood vessel growth by different antiangiogenic agents has become one of the most important topics in cancer research over the past few decades. The in vitro studies of these drugs are promising, but both the in vivo and the clinical experiences are controversial. Therefore, investigating the pharmacokinetic parameters of these compounds is a pivotal issue in drug development. In this study, the detection and the adsorption, distribution, metabolism, elimination (ADME) of the antiangiogenic receptor tyrosine kinase inhibitor (RTKI) sunitinib is analyzed in a subcutaneous syngeneic murine tumor model of colorectal cancer. The parent molecule of sunitinib was detected at m/z 399.218 with fragment ions at m/z 326.1 and 283.1 with matrix assisted laser desorption ionization (MALDI) technique. Metabolites of the drug were measured in blood samples and main metabolites were found in tumor, liver and kidney tissues at m/z 371.188, 397.203 and 415.214. Tissue distribution of the drug and its metabolites showed an overlapping pattern by MALDI imaging. The present study supports the role of the MALDI technique in the ADME characterization of drug candidates in preclinical drug development. (Less)
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type
Contribution to journal
publication status
published
subject
keywords
sunitinib, MALDI, imaging, mass spectrometry, angiogenesis, RTKI
in
British Journal of Pharmacology
volume
172
issue
4
pages
1148 - 1163
publisher
The British Pharmacological Society
external identifiers
  • pmid:25363319
  • wos:000348507700015
  • scopus:84921667759
ISSN
1476-5381
DOI
10.1111/bph.12990
language
English
LU publication?
yes
id
60db3e98-3a29-48d9-a21e-750d03637244 (old id 4699047)
date added to LUP
2014-11-21 13:05:24
date last changed
2017-10-01 04:06:16
@article{60db3e98-3a29-48d9-a21e-750d03637244,
  abstract     = {A functional blood vessel network is essential for maintaining the necessary oxygen and nutrient levels in solid tumors. Thus, the inhibition of blood vessel growth by different antiangiogenic agents has become one of the most important topics in cancer research over the past few decades. The in vitro studies of these drugs are promising, but both the in vivo and the clinical experiences are controversial. Therefore, investigating the pharmacokinetic parameters of these compounds is a pivotal issue in drug development. In this study, the detection and the adsorption, distribution, metabolism, elimination (ADME) of the antiangiogenic receptor tyrosine kinase inhibitor (RTKI) sunitinib is analyzed in a subcutaneous syngeneic murine tumor model of colorectal cancer. The parent molecule of sunitinib was detected at m/z 399.218 with fragment ions at m/z 326.1 and 283.1 with matrix assisted laser desorption ionization (MALDI) technique. Metabolites of the drug were measured in blood samples and main metabolites were found in tumor, liver and kidney tissues at m/z 371.188, 397.203 and 415.214. Tissue distribution of the drug and its metabolites showed an overlapping pattern by MALDI imaging. The present study supports the role of the MALDI technique in the ADME characterization of drug candidates in preclinical drug development.},
  author       = {Török, Szilvia and Végvári, Ákos and Rezeli, Melinda and Fehniger, Thomas and Tóvári, József and Paku, Sándor and László, Viktória and Hegedüs, Balázs and Rózsás, Anita and Döme, Balázs and Marko-Varga, György},
  issn         = {1476-5381},
  keyword      = {sunitinib,MALDI,imaging,mass spectrometry,angiogenesis,RTKI},
  language     = {eng},
  number       = {4},
  pages        = {1148--1163},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Localization of sunitinib, its metabolites and its target receptors in tumor bearing mice: a MALDI mass spectrometry imaging study},
  url          = {http://dx.doi.org/10.1111/bph.12990},
  volume       = {172},
  year         = {2015},
}