title: Human metabolites and transformation products of cyclophosphamide and ifosfamide: analysis, occurrence and formation during abiotic treatments.
abstract: This study describes a gas chromatography-mass spectrometry analytical method for the analysis of cytostatic cyclophosphamide (CP), ifosfamide (IF) and their selected metabolites/transformation products (TPs): carboxy-cyclophosphamide (carboxy-CP), keto-cyclophosphamide (keto-CP) and 3-dechloroethyl-ifosfamide/N-dechloroethyl-cyclophosphamide (N-decl-CP) in wastewater (WW). Keto-cyclophosphamide, CP and IF were extracted with Oasis HLB and N-decl-CP and carboxy-CP with Isolute ENV+ cartridges. Analyte derivatization was performed by silylation (metabolites/TPs) and acetylation (CP and IF). The recoveries and LOQs of the developed method were 58, 87 and 103 % and 77.7, 43.7 and 6.7 ng L(-1) for carboxy-CP, keto-CP and N-decl-CP, respectively. After validation, the analytical method was applied to hospital WW and influent and effluent samples of a receiving WW treatment plant. In hospital WW, levels up to 2690, 47.0, 13,200, 2100 and 178 ng L(-1) were detected for CP, IF, carboxy-CP, N-decl-CP and keto-CP, respectively, while in influent and effluent samples concentrations were below LOQs. The formation of TPs during abiotic treatments was also studied. Liquid chromatography-high-resolution mass spectrometry was used to identify CP and IF TPs in ultrapure water, treated with UV and UV/H2O2. UV treatment produced four CP TPs and four IF TPs, while UV/H2O2 resulted in five CPs and four IF TPs. Besides already known TPs, three novel TPs (CP-TP138a, imino-ifosfamide and IF-TP138) have been tentatively identified. In hospital WW treated by UV/O3/H2O2, none of the target metabolites/TPs resulted above LOQs.
authors.affiliation: Jožef Stefan Institute, Jamova cesta 39, 1000, Ljubljana, Slovenia.|Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000, Ljubljana, Slovenia.
authors.forename: Marjeta
authors.initials: M
authors.lastname: Česen
authors.affiliation: Jožef Stefan Institute, Jamova cesta 39, 1000, Ljubljana, Slovenia.|Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000, Ljubljana, Slovenia.
authors.forename: Tina
authors.initials: T
authors.lastname: Kosjek
authors.affiliation: Curtin Water Quality Research Centre (CWQRC), Curtin University, GPO Box U1987, Perth, WA, 6845, Australia.
authors.forename: Francesco
authors.initials: F
authors.lastname: Busetti
authors.affiliation: Faculty of Civil and Geodetic Engineering, University of Ljubljana, Hajdrihova 28, 1000, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Kompare
authors.affiliation: Jožef Stefan Institute, Jamova cesta 39, 1000, Ljubljana, Slovenia. ester.heath@ijs.si.|Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000, Ljubljana, Slovenia. ester.heath@ijs.si.
authors.forename: Ester
authors.initials: E
authors.lastname: Heath
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000032:analysis* / Q000378:metabolism; D003520:Cyclophosphamide / Q000032:analysis* / Q000378:metabolism; D004784:Environmental Monitoring / Q000379:methods*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007069:Ifosfamide / Q000032:analysis* / Q000378:metabolism; D062065:Wastewater / Q000032:analysis*; D014874:Water Pollutants, Chemical / Q000032:analysis* / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D007069:Ifosfamide; D062065:Wastewater; D014874:Water Pollutants, Chemical
keywords: Abiotic treatment; Cyclophosphamide; Cytostatic; Ifosfamide; Metabolites; Occurrence; Transformation products; Wastewater