Development of an analytical method for the determination of anthracyclines in hospital effluents

ArticleinChemosphere 65(8):1419-25 · November 2006with17 Reads
DOI: 10.1016/j.chemosphere.2006.03.069 · Source: PubMed
Little is known about the fate of cytostatics after their elimination from humans into the environment. Being often very toxic compounds, their quantification in hospital effluents may be necessary to individualise the putative magnitude of pollution problems. We therefore developed a method for the determination of the very important group of anthracyclines (doxorubicin, epirubicin, and daunorubicin) in hospital effluents. Waste water samples were enriched by solid phase extraction (concentration factor 100), analysed by reversed-phase high performance liquid chromatography (RP-HPLC), and monitored by fluorescence detection. This method is reproducible and accurate within a range of 0.1-5 micro g l(-1) for all compounds (limits of quantification: 0.26-0.29 micro g l(-1) ; recoveries >80%). The applicability of the method was proven by chemical analysis of hospital sewage samples (range: 0.1-1.4 micro g l(-1) epirubicin and 0.1-0.5 micro g l(-1) doxorubicin). Obtained over a time period of one month, the results were in line with those calculated by an input-output model. These investigations show that the examined cytostatics are easily detectable and that the presented method is suitable to estimate the dimension of pharmaceutical contamination originating from hospital effluents.
    • "In humans, doxorubicin can also have adverse effects on the gastrointestinal tract, mainly manifesting as severe mucositis , which usually resolves in 10 days (Tacar et al., 2013). In this study, we also measured the plasma levels of doxorubicinol, the major metabolite of doxorubicin (Thorn et al., 2011), which is considered to be 10 times more cytotoxic than doxorubicin (Mahnik et al., 2006). It is postulated to be the main cause for the cardiotoxic effects of doxorubicin (Olson et al., 1988), although it has a reduced anticancer effect compared with doxorubicin (Ferrazzi et al., 1991). "
    [Show abstract] [Hide abstract] ABSTRACT: Doxorubicin can cause life-threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Göttingen minipig is an accepted species for non-clinical safety assessment and translation to man, we aimed at exploring its use as a non-rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Göttingen minipigs received 1.5 mg kg(-1) , 3/2.3 mg kg(-1) or vehicle at intervals of 3 weeks for 7 cycles. Doxorubicin treatment resulted in a dose-related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose-related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi-thin sections showed the presence of dose-related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high-dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Göttingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non-rodent species of choice for studies on doxorubicin toxicity. Copyright © 2015 John Wiley & Sons, Ltd.
    Article · Nov 2015
    • "It is well known that DOX is enzymatically reduced to a number of metabolites [24]. The reduction of DOX to its major metabolite, DOXol [25] by way of carbonyl reductase-1 [26], carbonyl reductase-3 [27] or aldo-keto reductases [28] is of particular clinical importance as it is 10 times more cytotoxic than DOX [29] and has been identified to be responsible for the cardiotoxic effect related to DOX therapy [4] . DOXol concentrations in the plasma did not have the same degree of variability within the dose groups or degree of dose response as that observed in the DOX concentrations. "
    [Show abstract] [Hide abstract] ABSTRACT: Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.
    Full-text · Article · Sep 2015
    • "Mass spectrometry is the most selective technique to identify unknown compounds and, using ESI-MS, it is possible to obtain structurally significant fragmentation ions [12][13][14][15][16][17]. With this in mind, in a previous work we have investigated the transformation of cyclofosfamide and mitomycin C [18], while in this work we focus on doxorubicin and methotrexate, whose presence was already documented in hospital effluents [17,19] or surface waters [20]. Though, only few studies investigate their biotic or abiotic transformation [21][22][23]. "
    [Show abstract] [Hide abstract] ABSTRACT: A study on the fate of two antineoplastic drugs, methotrexate and doxorubicin, in the aquatic environment is presented. The investigation involved a study of their decomposition under dark experiments, homogeneous photolysis and heterogeneous photocatalysis using titanium dioxide, the identification of intermediate compounds, as well as the assessment of acute toxicity over time. The analysis were carried out using LC (ESI positive mode) coupled with LTQ-Orbitrap analyser; accurate mass-to-charge ratios of parent ions were reported with inaccuracy below 10mmu, which guarantee the correct assignment of their molecular formula in all cases, while their MS(2) and MS(3) spectra showed several structural-diagnostic ions that allowed to characterize the different transformation products and to discriminate the isobaric species. Fourteen and eight main species were identified subsequently to doxorubicin or methotrexate transformation. The major transformation processes for doxorubicin involved (poli)hydroxylation and/or oxidation of the molecule, or the detachment of the sugar moiety. Methotrexate transformation involved decarboxylation or the molecule cleavage. Acute toxicity measurements showed that not only the two drugs exhibit high toxicity, but also their initial transformation products are highly toxic.
    Article · Aug 2014
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