title: Speciation analysis of bromine-containing drug metabolites in feces samples from a human in vivo study by means of HPLC/ICP-MS combined with on-line isotope dilution.
abstract: The aim of this work was speciation analysis of metabolites in feces samples collected within a clinical study during which a bromine-containing anti-tuberculosis drug (TMC207) was administered to patients with multi-drug resistant tuberculosis infection. Owing to slow elimination of the drug, no (14)C label was used within this study. Quantification of the bromine species was accomplished using high performance liquid chromatography coupled to inductively coupled plasma-mass spectrometry (HPLC/ICP-MS) in combination with on-line isotope dilution (on-line ID), while structural elucidation of the species was performed using HPLC coupled to electrospray ionization-mass spectrometry. The ICP-MS-based method developed shows a good intra- and inter-day reproducibility (relative standard deviation = 3.5%, N = 9); the limit of detection (1.5 mg TMC207 L(-1)) is of the same order of magnitude as that for HPLC/radiodetection; the dynamic range of the method covers more than two orders of magnitude. Furthermore, the column recovery was demonstrated to be quantitative (recoveries between 90.6% and 99.5%). Based on the excellent figures of merit, the "cold" HPLC/ICP-MS approach could be deployed for the actual human in vivo metabolism study, such that exposure of the human volunteers to the (14)C radiolabel was avoided.
authors.affiliation: Department of Analytical Chemistry, Ghent University, Ghent, Belgium.
authors.forename: Björn
authors.initials: B
authors.lastname: Meermann
authors.forename: Marc
authors.initials: M
authors.lastname: Bockx
authors.forename: Aline
authors.initials: A
authors.lastname: Laenen
authors.forename: Cis
authors.initials: C
authors.lastname: Van Looveren
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.forename: Frank
authors.initials: F
authors.lastname: Vanhaecke
mesh_terms: D000995:Antitubercular Agents / Q000032:analysis / Q000378:metabolism* / Q000627:therapeutic use; D001966:Bromine / Q000032:analysis; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000032:analysis; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D064687:Diarylquinolines; D005243:Feces / Q000737:chemistry*; D005260:Female; D006801:Humans; D007201:Indicator Dilution Techniques; D007554:Isotopes / Q000032:analysis; D008297:Male; D011804:Quinolines / Q000032:analysis / Q000378:metabolism* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D002250:Carbon Radioisotopes; D064687:Diarylquinolines; D007554:Isotopes; D011804:Quinolines; C493870:bedaquiline; D001966:Bromine