title: Use of the bromine isotope ratio in HPLC-ICP-MS and HPLC-ESI-MS analysis of a new drug in development.
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 (79)Br/(81)Br 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 MS(2) spectra obtained using the Q-Tof Ultima mass spectrometer or MS(n) 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.
authors.affiliation: Global Preclinical Development, Johnson & Johnson Pharmaceutical R&D, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.forename: Lieve I L
authors.initials: LI
authors.lastname: Balcaen
authors.forename: Kenny
authors.initials: K
authors.lastname: De Wolf
authors.forename: Bjorn
authors.initials: B
authors.lastname: De Samber
authors.forename: Cis
authors.initials: C
authors.lastname: Van Looveren
authors.forename: Rob
authors.initials: R
authors.lastname: Hurkmans
authors.forename: Frank
authors.initials: F
authors.lastname: Vanhaecke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000032:analysis* / Q000378:metabolism; D001966:Bromine / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D064687:Diarylquinolines; D004285:Dogs; D015195:Drug Design; D007554:Isotopes; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D015394:Molecular Structure; D011804:Quinolines / Q000008:administration & dosage / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D007554:Isotopes; D011804:Quinolines; C493870:bedaquiline; D001966:Bromine