The occurrence of toxic drug residues is a hot topic concerning emerging environmental contaminants. The occupational exposure to anticancer drugs could be severe for health-care personnel and general public attending potentially polluted areas (such as oncology departments of hospitals) because of high therapeutic concentrations. The aim of this work was to generate degradation compounds similar to those formed in metabolic or environmental pathways by adopting a photocatalytic process and to identify them in indoor environments alongside parent compounds. A photodegradation model was applied to cyclophosphamide and mitomycin C. Studied substances and degradants were quantified in environmental samples by liquid chromatography with multiple-stage mass spectrometry (LC–MS n ) analysis using an orbital trap instrument with an electrospray interface. Various oxidative degradants were formed using the photocatalytic simulation model of degradation of antineoplastic drugs, beside some hydrolysis and molecule breakdown subproducts. High resolution MS n spectra were used to identify and confirm the proposed structures. Kinetics of formation of the main degradation products were also studied.
The frequency of recognition of toxic drug residues is an important issue concerning emerging environmental contaminants. This problem is also exacerbated by the low therapeutic index of drugs used in cancer chemotherapy. The occupational exposure to residues of anticancer drugs must be kept under strict control by safety managers because it could be severe for health care personnel and general public attending potentially polluted areas (such as oncology departments and pharmacies of hospitals) because of high therapeutic concentrations. In addition, urinary elimination by patients represents a source of contamination. The monitoring of drug residues is necessary to guarantee occupational safety and the absence of pollution. The presence of anticancer drug residues in environmental water samples has been reported (1–3). Looking closer at the structural features of these compounds, it is possible to see that the majority of chemotherapeutic drugs hold molecular structures with a high chemical reactivity (4). As a consequence of this great aptitude to undergo chemical transformation, it could be difficult to record measurable levels of some of these drugs. As an example, in a previous study (5) we found evidence of the difficulty to recover traces of mitomycin C because of its low stability. The aim of this work is to generate degradation compounds similar to those formed in metabolic or environmental pathways by adopting a photocatalytic process and to identify them in indoor environments. An additional purpose of this study is to develop a selective and sensitive method as a tool to detect drug transformation and degradation products and to quantify them in biological and environmental samples, beside parent compounds.
In this work, two anticancer drugs were studied: the N-mustard cyclophosphamide (N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) and the aziridine mitomycin C ([(1aS,8S,8aR,8bS)-6-amino-8a-methoxy-5-methyl-4,7-dioxo-1,1a,2,4,7,8,8a,8b-octahydroazireno[2',3':3,4]pyrrolo[1,2-a]indol-8-yl]methyl carbamate). We chose cyclophosphamide and mitomycin C because of the popular use of these drugs and because of their different stability. The photodecomposition of drugs was carried out by heterogeneous photocatalysis, using titanium dioxide in water as previously reported (6,7). By this process, the photodecomposition of drugs could be due to either oxidative species or reductive conduction band electrons (8,9).A highly sensitive method was developed to measure the degradation products in wipe samples that allows detection of parent drugs at the nanogram level (5). Occupational exposure monitoring of these drugs shows frequent cyclophosphamide positive measurements but no significant mitomycin C determination. The high instability of the mitomycin molecule is probably the main cause of these findings. One of the targets of this work is to identify new possible markers of mitomycin in environmental pollution. Identification and characterization of degradation compounds could contribute significantly to the development of more effective analytical methods to monitor occupational exposure.
High performance liquid chromatography (HPLC) coupled to mass spectrometry (MS) via an electrospray ionization (ESI) interface is a powerful tool to identify and measure anticancer drugs in the environment (10), especially in health care settings (11). However, liquid chromatography—mass spectrometry (LC–MS) analysis performed in full-scan mode is not sensitive enough to detect and characterize metabolites at trace levels and the excellent sensitivity provided in multiple reaction monitoring (MRM) mode suffers from a lack of structural information to characterize the huge number of potential degradants formed from drug compounds.
For this reason, we developed a sensitive liquid chromatography–high-resolution mass spectrometry (LC–HRMS) methodology using orbital trap technology (12) with the purpose of exploiting the potential of untargeted analysis for which it is fitted. From the analysis of spectra acquired at high resolving power, it was possible to hypothesize the structure of the main degradation products observed in the photocatalysis simulation model.