title: Multianalyte determination of 24 cytostatics and metabolites by liquid chromatography-electrospray-tandem mass spectrometry and study of their stability and optimum storage conditions in aqueous solution.
abstract: A multianalyte liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) method for determination of 19 cytostatics and 5 metabolites, from 6 different therapeutic families, has been developed, and the structures of the main characteristic fragment ions have been proposed. Instrumental limits of detection and quantification are in the range 0.1-10.3 and 1.0-34.3 ng mL(-1), respectively. Moreover, the stability of the compounds in aqueous solution was investigated in order to establish the best conditions for preparation and storage of both calibration standards and water samples. Dimethylsulphoxide (DMSO) was selected as solvent for preparation of the stock solutions. At room temperature (25 °C), 11 of the 24 target compounds were shown to be unstable in water (percentage of organic solvent 4%), with concentration losses greater than 20% in less than 24 h. At 4 °C (typical storage temperature for water samples) all compounds, except MTIC and chlorambucil, were stable for 24h, but the number of stable compounds decreased to 10 after 9 days. Freezing of the aqueous solutions improved considerably the stability of various compounds: after 3 months of storage at -20 °C, 10 compounds, namely, 5-fluorouracil, carboplatin, gemcitabine, temozolomide, vincristine, vinorelbine, ifosfamide, cyclophosphamide, etoposide, and capecitabine, remained stable (in contrast to only carboplatin and capecitabine at 4 °C). The addition of acid improved the stability of methotrexate and its metabolite hydroxy-methotrexate but not that of the rest of compounds. The addition of organic solvent (50% methanol or DMSO) prevented the degradation at 4 °C of the otherwise unstable compounds oxaliplatin, methotrexate, erlotinib, doxorubicin, tamoxifen, and paclitaxel. To the authors' knowledge, five of the analytes investigated have never been searched for in the aquatic environment (imatinib, 6α-hydroxypaclitaxel, endoxifen, (Z)4-hydroxytamoxifen, and temozolomide), and for many of them the stability data provided, and even the analytical LC-MS/MS conditions, are the first ever published.
authors.affiliation: Water and Soil Quality Research Group, Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Negreira
authors.forename: Nicola
authors.initials: N
authors.lastname: Mastroianni
authors.forename: Miren
authors.initials: M
authors.lastname: López de Alda
authors.forename: Damià
authors.initials: D
authors.lastname: Barceló
mesh_terms: D000470:Alkaloids / Q000302:isolation & purification*; D000964:Antimetabolites, Antineoplastic / Q000302:isolation & purification*; D018906:Antineoplastic Agents, Alkylating / Q000302:isolation & purification*; D002138:Calibration; D002853:Chromatography, Liquid; D054697:Cytostatic Agents / Q000302:isolation & purification*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D012996:Solutions; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014867:Water
chemical_list: D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D054697:Cytostatic Agents; D012996:Solutions; D014867:Water; D004121:Dimethyl Sulfoxide
keywords: Cytostatics; Electrospray; Fragmentation; Liquid chromatography–mass spectrometry; Stability; Water samples