Human metabolites and transformation products of cyclophosphamide and ifosfamide: analysis, occurrence and formation during abiotic treatments

Česen, Marjeta; Kosjek, Tina; Busetti, Francesco; Kompare, Boris; Heath, Ester

Human metabolites and transformation products of cyclophosphamide and ifosfamide: analysis, occurrence and formation during abiotic treatments

2016

Česen, Marjeta | Kosjek, Tina | Busetti, Francesco | Kompare, Boris | Heath, Ester

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.

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