Use of the bromine isotope ratio in HPLC-ICP-MS and HPLC-ESI-MS analysis of a new drug in development |
| |
Authors: | Filip Cuyckens Lieve I L Balcaen Kenny De Wolf Bjorn De Samber Cis Van Looveren Rob Hurkmans Frank Vanhaecke |
| |
Institution: | (1) Global Preclinical Development, Johnson & Johnson Pharmaceutical R&D, Turnhoutseweg 30, 2340 Beerse, Belgium;(2) Department of Analytical Chemistry, Ghent University, Krijgslaan 281-S12, 9000 Ghent, Belgium |
| |
Abstract: | A combination of inductively coupled plasma mass spectrometry (ICP-MS) and electrospray ionization mass spectrometry (ESI-MS)
was deployed for the metabolite profiling and metabolite identification of a new antituberculosis compound (R207910, also
known as TMC207) that is currently in drug development. R207910 contains one bromine atom, allowing the detection by ICP-MS.
Fluctuations in the Br sensitivity caused by the HPLC gradient were counteracted by the use of species-unspecific isotope
dilution. In order to evaluate the method developed, the results obtained were compared with those acquired via radioactivity
detection. HPLC-ESI-MS was used for the structural identification of R207910 and its metabolites. The 79Br/81Br isotope ratio is also valuable in the search for metabolites in the complex background of endogenous compounds obtained
using HPLC-ESI-MS analyses. Data-dependent scanning using isotope recognition with an ion trap mass spectrometer or processing
of Q-Tof data provides HPLC-ICP-MS-like “bromatograms”. The combination of accurate mass measurements and the fragmentation
behavior in the MS2 spectra obtained using the Q-Tof Ultima mass spectrometer or MSn spectra acquired using the LTQ-Orbitrap allowed structural characterization of the main metabolites of R207910 in methanolic
dog and rat faeces extracts taken 0–24 h post-dose.
Figure Analyses of a rat faeces extract taken 0–24 h post-dose: a HPLC-ICP-MS using isotope dilution, b corresponding Br mass flow chromatogram, c radio-HPLC, d Q-Tof ESI-MS TIC, e Q-Tof ESI-MS bromatogram after Br stripping, f LTQ-Orbitrap ESI-MS2 TIC obtained with isotopic-data-dependent scanning |
| |
Keywords: | HPLC-ICP-MS HPLC-ESI-MS Metabolite profiling Metabolite identification Bromine Isotopic-data-dependent scanning |
本文献已被 PubMed SpringerLink 等数据库收录! |
|