Fluorouracil in the environment: Analysis, occurrence, degradation and transformation

Kosjek, Tina; Perko, Silva; Žigon, Dušan; Heath, Ester

doi:10.1016/j.chroma.2013.03.046

Cited by 123 publications

(65 citation statements)

References 21 publications

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“…The average pH values were acidic and within a range acceptable for topical application. This was a favorable pH as 5-fluorouracil is a weakly acidic drug with an acid dissociation constant (pKa) of 8.0 (26). As calculated according to the Henderson-Hasselbalch equation, 98% of the drug in the 5-fluorouracil lotions was unionized and 96% of the drug in the 5-fluorouracil Pheroid™ lotions was unionized at the pH of the formulations.…”

Section: Physicochemical Characterization Of Formulationsmentioning

confidence: 96%

Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma

et al. 2015

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Abstract. Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceutical ingredient (API). In this study, the influence of Pheroid™ technology, which is a unique colloidal drug delivery system, on the skin permeation and antimelanoma efficacy of 5-fluorouracil were investigated. Lotions containing Pheroid™ with different concentrations of 5-fluorouracil were formulated then used in Franz cell skin diffusion studies and tape stripping. The in vitro efficacy of 5-fluorouracil against human melanoma cells (A375) was investigated using a flow cytometric apoptosis assay. Statistically significant concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in an enhanced in vitro skin permeation from the 4.0% 5-fluorouracil lotion (p<0.05). The stratum corneum-epidermis and epidermis-dermis retained 5-fluorouracil concentrations of 2.31 and 6.69 μg/ml, respectively, after a diffusion study with the 4.0% Pheroid™ lotion. Subsequent to the apoptosis assay, significant differences were observed between the effect of 13.33 μg/ml 5-fluorouracil in Pheroid™ lotion and the effects of the controls. The results obtained suggest that the Pheroid™ drug delivery system possibly enhances the flux and delivery of 5-fluorouracil into the skin. Therefore, using Pheroid™ could possibly be advantageous with respect to topical delivery of 5-fluorouracil.

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Section: Physicochemical Characterization Of Formulationsmentioning

confidence: 96%

Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma

et al. 2015

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“…Anticancer concentrations in mixture ranged from tenths of ng/L to hundreds of μg/L, which represent comparable concentration ranges than have been previously measured in wastewater. 5-FU was found in the hospital and municipal wastewaters at concentrations in the range <5 ng/ L to 124 μg/L (Mahnik et al 2004Kovalova et al 2009;Kosjek et al 2013);CDDP was detected, as Pt compound, at concentrations in the range of 2-250 μg/L (Lenz (Yin et al 2010;FerrandoCliment et al 2014); IM concentrations in aquatic systems are not known to date, probably because its occurrence is below the limit of detection (36-54 ng/L) (Negreira et al 2013(Negreira et al , 2014. However, Besse et al (2012) estimated environmental concentration for this drug in France, based on excretion rates, at 5 ng/L.…”

Section: Resultsmentioning

confidence: 99%

Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures

Kundi

Parrella²,

Lavorgna³

et al. 2015

Environ Sci Pollut Res

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The combined genotoxic effects of four anticancer drugs (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]) were studied testing their binary mixtures in two crustaceans that are part of the freshwater food chain, namely Daphnia magna and Ceriodaphnia dubia. Genotoxicity was assessed using the in vivo comet assay. Assessment was based on two distinct effect sizes determined from dose-response experiments. Doses for single and combined exposures expected to result in these effect sizes were computed based on Bliss independence as reference model. Statistical comparison by analysis of variance of single and combined toxicities allowed accepting or rejecting the independency hypothesis. The results obtained for D. magna showed independent action for all mixtures except for IM+5-FU that showed an antagonistic interaction. In C. dubia, most mixtures had antagonist interactions except IM+5-FU and IM+CDDP that showed Bliss independence. Despite the antagonistic interactions, our results demonstrated that combinations of anticancer drugs could be of environmental concern because effects occur at very low concentrations that are in the range of concentrations encountered in aquatic systems.

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“…Until recently, scientists did not have the technology nor the know-how to measure environmental levels of anticancer drugs and only a limited number of laboratories worldwide are analysing them in environmental and wastewater samples (Česen et al 2015;Ferrando-Climent et al 2014, 2013Kosjek and Heath 2011;Kosjek et al 2015Kosjek et al , 2013Llewellyn et al 2011;Negreira et al 2014aNegreira et al , 2013aParrella et al 2014). One reason is their low environmental levels (≤ ng L −1 ), which require the very latest in modern analytical instrumentation, and possibly their toxicity makes laboratories reluctant to analyse these compounds since additional safety protocols and waste collection must be in place.…”

Section: Introductionmentioning

confidence: 97%

First inter-laboratory comparison exercise for the determination of anticancer drugs in aqueous samples

Heath

Česen

Negreira

et al. 2015

Environ Sci Pollut Res

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The results of an inter-laboratory comparison exercise to determine cytostatic anticancer drug residues in surface water, hospital wastewater and wastewater treatment plant effluent are reported. To obtain a critical number of participants, an invitation was sent out to potential laboratories identified to have the necessary knowledge and instrumentation. Nine laboratories worldwide confirmed their participation in the exercise. The compounds selected (based on the extent of use and laboratories capabilities) included cyclophosphamide, ifosfamide, 5-fluorouracil, gemcitabine, etoposide, methotrexate and cisplatinum. Samples of spiked waste (hospital and wastewater treatment plant effluent) and surface water, and additional non-spiked hospital wastewater, were prepared by the organising laboratory (Jožef Stefan Institute) and sent out to each participant partner for analysis. All analytical methods included solid phase extraction (SPE) and the use of surrogate/internal standards for quantification. Chemical analysis was performed using either liquid or gas chromatography mass (MS) or tandem mass (MS/MS) spectrometry. Cisplatinum was determined using inductively coupled plasma mass spectrometry (ICP-MS). A required minimum contribution of five laboratories meant that only cyclophosphamide, ifosfamide, methotrexate and etoposide could be included in the statistical evaluation. z-score and Q test revealed 3 and 4 outliers using classical and robust approach, respectively. The smallest absolute differences between the spiked values and the measured values were observed in the surface water matrix. The highest within-laboratory repeatability was observed for methotrexate in all three matrices (CV ≤ 12 %). Overall, inter-laboratory reproducibility was poor for all compounds and matrices (CV 27-143 %) with the only exception being methotrexate measured in the spiked hospital wastewater (CV = 8 %). Random and total errors were identified by means of Youden plots.

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Fluorouracil in the environment: Analysis, occurrence, degradation and transformation

Cited by 123 publications

References 21 publications

Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma

Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma

Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures

First inter-laboratory comparison exercise for the determination of anticancer drugs in aqueous samples

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