Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity

Highlights

Specific second-order rate constants were determined for 5-FU and CAP with ozone.

Reaction sites were confirmed by kinetics, Fukui analysis, and products.

The olefin moiety was the main ozone reaction site for 5-FU and CAP.

Carboxylic acids comprised most of the residual TOC for 5-FU.

Ozonation removed the toxicity associated with 5-FU and products but not CAP.

Abstract

Anticancer drugs (ADs) have been detected in the environment and represent a risk to aquatic organisms, necessitating AD removal in drinking water and wastewater treatment. In this study, ozonation of the most commonly used antimetabolite ADs, namely 5-fluorouracil (5-FU) and its prodrug capecitabine (CAP), was investigated to determine reaction kinetics, oxidation mechanisms, and residual toxicity. The specific second-order rate constants between aqueous ozone and 5-FU, 5-FU⁻, 5-FU²⁻, CAP, and CAP⁻ were determined to be 7.07(±0.11)×10⁴ M⁻¹·s⁻¹, 1.36(±0.06)×10⁶ M⁻¹·s⁻¹, 2.62(±0.17)×10⁷ M⁻¹·s⁻¹, 9.69(±0.08)×10³ M⁻¹·s⁻¹, and 4.28(±0.07)×10⁵ M⁻¹·s⁻¹, respectively; furthermore, the second-order rate constants for ^•OH reaction with 5-FU and CAP at pH 7 were determined to be 1.85(±0.20)×10⁹ M⁻¹·s⁻¹ and 9.95(±0.26)×10⁹ M⁻¹·s⁻¹, respectively. Density functional theory was used to predict the main ozone reaction sites of 5-FU (olefin) and CAP (olefin and deprotonated secondary amine), and these mechanisms were supported by the identified transformation products. Carboxylic acids constituted a majority of the residual organic matter for 5-FU ozonation; however, carboxylic acids and aldehydes were important components of the residual organic matter generated by CAP. Ozone removed the toxicity of 5-FU to Vibrio fischeri, but the residual toxicity of ozonated CAP solutions exhibited an initial increase before subsequent removal. Ultimately, these results suggest that ozone is a suitable technology for treatment of 5-FU and CAP, although the residual toxicity of transformation products must be carefully considered.

Graphical abstract

Keywords

Ozone / 5-fluorouracil / Capecitabine / Hydroxyl radicals / Chemotherapy agents / Toxicity

References

[1] Azuma T, Ishiuchi H, Inoyama T, Teranishi Y, Yamaoka M, Sato T, Mino Y (2015). Occurrence and fate of selected anticancer, antimicrobial, and psychotropic pharmaceuticals in an urban river in a subcatchment of the Yodo River basin, Japan. Environmental Science and Pollution Research International, 22(23): 18676–18686

[2] Bao Y, Deng S, Jiang X, Qu Y, He Y, Liu L, Chai Q, Mumtaz M, Huang J, Cagnetta G, Yu G (2018). Degradation of PFOA substitute: GenX (HFPO–DA Ammonium Salt): Oxidation with UV/Persulfate or reduction with UV/Sulfite? Environmental Science & Technology, 52(20): 11728–11734

[3] Beltrán F J, Aguinaco A, García-Araya J F (2009). Mechanism and kinetics of sulfamethoxazole photocatalytic ozonation in water. Water Research, 43(5): 1359–1369

[4] Besse J P, Latour J F, Garric J (2012). Anticancer drugs in surface waters: What can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs? Environment International, 39(1): 73–86

[5] Blaney L, Lawler D F, Katz L E (2019). Transformation kinetics of cyclophosphamide and ifosfamide by ozone and hydroxyl radicals using continuous oxidant addition reactors. Journal of Hazardous Materials, 364: 752–761

[6] Blicharska B, Kupka T (2002). Theoretical DFT and experimental NMR studies on uracil and 5-fluorouracil. Journal of Molecular Structure, 613(1–3): 153–166

[7] Booker V, Halsall C, Llewellyn N, Johnson A, Williams R (2014). Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Science of the Total Environment, 473–474: 159–170

[8] Bui X T, Vo T P, Ngo H H, Guo W S, Nguyen T T (2016). Multicriteria assessment of advanced treatment technologies for micropollutants removal at large-scale applications. Science of the Total Environment, 563–564: 1050–1067

[9] Buxton G V, Greenstock C L, Helman W P, Ross A B (1988). Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (⋅OH/⋅O) in aqueous solution. Journal of Physical and Chemical Reference Data, 17(2): 513–886

[10] Chang J, Chen Z L, Wang Z, Shen J M, Chen Q, Kang J, Yang L, Liu X W, Nie C X (2014). Ozonation degradation of microcystin-LR in aqueous solution: intermediates, byproducts and pathways. Water Research, 63: 52–61

[11] Chen P, Wang F, Chen Z, Zhang Q, Su Y, Shen L, Yao K, Liu Y, Cai Z, Lv W, Liu G (2017). Study on the photocatalytic mechanism and detoxicity of gemfibrozil by a sunlight-driven TiO₂/carbon dots photocatalyst: The significant roles of reactive oxygen species. Applied Catalysis B: Environmental, 204: 250–259

[12] Cruz-Alcalde A, Sans C, Esplugas S (2017). Priority pesticides abatement by advanced water technologies: The case of acetamiprid removal by ozonation. Science of the Total Environment, 599–600: 1454–1461

[13] Deanna N (2018). Global Oncology Trends 2018. Parsippany: IQVIA Institute for Human Data Science

[14] Deborde M, Rabouan S, Duguet J P, Legube B (2005). Kinetics of aqueous ozone-induced oxidation of some endocrine disruptors. Environmental Science & Technology, 39(16): 6086–6092

[15] Elovitz M S, Shemer H, Peller J R, Vinodgopal K, Sivaganesan M, Linden K G (2008). Hydroxyl radical rate constants: comparing UV/H₂O₂ and pulse radiolysis for environmental pollutants. Journal of Water Supply: Research & Technology- Aqua, 57(6): 391–401

[16] Elovitz M S, von Gunten U, Kaiser H (2000). Hydroxyl radical/ozone ratios during ozonation processes. II. The effect of temperature, pH, alkalinity, and DOM properties. Ozone Science and Engineering, 22(2): 123–150

[17] Faria P C C, Órfão J J M, Pereira M F R (2008). Activated carbon catalytic ozonation of oxamic and oxalic acids. Applied Catalysis B: Environmental, 79(3): 237–243

[18] Ferre-Aracil J, Valcárcel Y, Negreira N, de Alda M L, Barceló D, Cardona S C, Navarro-Laboulais J (2016). Ozonation of hospital raw wastewaters for cytostatic compounds removal. Kinetic modelling and economic assessment of the process. Science of the Total Environment, 556: 70–79

[19] Flyunt R, Theruvathu J A, Leitzke A, von Sonntag C (2002). The reactions of thymine and thymidine with ozone. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry, 9: 1572–1582

[20] Franquet-Griell H, Gómez-Canela C, Ventura F, Lacorte S (2015). Predicting concentrations of cytostatic drugs in sewage effluents and surface waters of Catalonia (NE Spain). Environmental Research, 138: 161–172

[21] Franquet-Griell H, Medina A, Sans C, Lacorte S (2017). Biological and photochemical degradation of cytostatic drugs under laboratory conditions. Journal of Hazardous Materials, 323(Pt A): 319–328

[22] Fu R, Tian L, Chen F (2014). Comparing methods for predicting the reactive site of electrophilic substitution. Wuli Huaxue Xuebao, 30(04): 628–639 (in Chinese)

[23] Gómez-Canela C, Bolivar-Subirats G, Tauler R, Lacorte S (2017). Powerful combination of analytical and chemometric methods for the photodegradation of 5-Fluorouracil. Journal of Pharmaceutical and Biomedical Analysis, 137: 33–41

[24] Gómez-Canela C, Ventura F, Caixach J, Lacorte S (2014). Occurrence of cytostatic compounds in hospital effluents and wastewaters, determined by liquid chromatography coupled to high-resolution mass spectrometry. Analytical and Bioanalytical Chemistry, 406(16): 3801–3814

[25] Gómez-Ramos M M, Mezcua M, Agüera A, Fernández-Alba A R, Gonzalo S, Rodríguez A, Rosal R (2011). Chemical and toxicological evolution of the antibiotic sulfamethoxazole under ozone treatment in water solution. Journal of Hazardous Materials, 192(1): 18–25

[26] Governo M, Santos M S F, Alves A, Madeira L M (2017). Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes. Environmental Science and Pollution Research International, 24(1): 844–854

[27] Guo R, Zheng F, Chen J (2015). Evaluation of the aquatic toxic effect varied during the degradation of capecitabine under the environmental abiotic and biotic processes. RSC Advances, 5(94): 76772–76778

[28] Heath E, Filipič M, Kosjek T, Isidori M (2016). Fate and effects of the residues of anticancer drugs in the environment. Environmental Science and Pollution Research International, 23(15): 14687–14691

[29] Hopkins Z R, Blaney L (2014). A novel approach to modeling the reaction kinetics of tetracycline antibiotics with aqueous ozone. Science of the Total Environment, 468–469: 337–344

[30] Hopkins Z R, Snowberger S, Blaney L (2017). Ozonation of the oxybenzone, octinoxate, and octocrylene UV-filters: Reaction kinetics, absorbance characteristics, and transformation products. Journal of Hazardous Materials, 338: 23–32

[31] Jin L, Lü M, Zhao C, Min S, Zhang T, Zhang Q (2017). The reactivity of the 5-formylcytosine with hydroxyl radical: A theoretical perspective. Journal of Physical Organic Chemistry, 30(11): e3691

[32] Jin X, Peldszus S, Huck P M (2012). Reaction kinetics of selected micropollutants in ozonation and advanced oxidation processes. Water Research, 46(19): 6519–6530

[33] Kosjek T, Heath E (2011). Occurrence, fate and determination of cytostatic pharmaceuticals in the environment. TrAC Trends in Analytical Chemistry, 30(7): 1065–1087

[34] Kosjek T, Perko S, Žigon D, Heath E (2013). Fluorouracil in the environment: Analysis, occurrence, degradation and transformation. Journal of Chromatography. A, 1290: 62–72

[35] Kovalova L (2009).Cytostatics in the aquatic environment: Analysis, occurrence, and possibilities for removal. Dissertation for the Doctoral Degree. Aachen: RWTH Aachen University

[36] Kuang J, Huang J, Wang B, Cao Q, Deng S, Yu G (2013). Ozonation of trimethoprim in aqueous solution: identification of reaction products and their toxicity. Water Research, 47(8): 2863–2872

[37] Kümmerer K, Haiß A, Schuster A, Hein A, Ebert I (2016). Antineoplastic compounds in the environment-substances of special concern. Environmental Science and Pollution Research International, 23(15): 14791–14804

[38] Lee Y, Kovalova L, McArdell C S, von Gunten U (2014). Prediction of micropollutant elimination during ozonation of a hospital wastewater effluent. Water Research, 64: 134–148

[39] Leitzke A, Sonntag C V (2009). Ozonolysis of unsaturated acids in aqueous solution: Acrylic, methacrylic, maleic, fumaric and muconic acids. Ozone Science and Engineering, 31(4): 301–308

[40] Li W, Nanaboina V, Chen F, Korshin G V (2016). Removal of polycyclic synthetic musks and antineoplastic drugs in ozonated wastewater: Quantitation based on the data of differential spectroscopy. Journal of Hazardous Materials, 304: 242–250

[41] Li W, Tanumihardja J, Masuyama T, Korshin G (2015). Examination of the kinetics of degradation of the antineoplastic drug 5-fluorouracil by chlorine and bromine. Journal of Hazardous Materials, 282: 125–132

[42] Lin A Y, Hsueh J H, Hong P K A (2015). Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation. Environmental Science and Pollution Research International, 22(1): 508–515

[43] Lin A Y, Wang X H, Lee W N (2013). Phototransformation determines the fate of 5-fluorouracil and cyclophosphamide in natural surface waters. Environmental Science & Technology, 47(9): 4104–4112

[44] Lin H H, Lin A Y (2014). Photocatalytic oxidation of 5-fluorouracil and cyclophosphamide via UV/TiO₂ in an aqueous environment. Water Research, 48: 559–568

[45] Liu T, Yin K, Liu C, Luo J, Crittenden J, Zhang W, Luo S, He Q, Deng Y, Liu H, Zhang D (2018). The role of reactive oxygen species and carbonate radical in oxcarbazepine degradation via UV, UV/H₂O₂: Kinetics, mechanisms and toxicity evaluation. Water Research, 147: 204–213

[46] Lutterbeck C A, Wilde M L, Baginska E, Leder C, Machado Ê L, Kümmerer K (2016). Degradation of cyclophosphamide and 5-fluorouracil by UV and simulated sunlight treatments: Assessment of the enhancement of the biodegradability and toxicity. Environmental Pollution, 208(Pt B): 467–476

[47] Mahnik S N, Lenz K, Weissenbacher N, Mader R M, Fuerhacker M (2007). Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system. Chemosphere, 66(1): 30–37

[48] Mahnik S N, Rizovski B, Fuerhacker M, Mader R M (2004). Determination of 5-fluorouracil in hospital effluents. Analytical and Bioanalytical Chemistry, 380(1): 31–35

[49] MarvinSketch (2018). MarvinSketch (version 18.23.0). Budapest: ChemAxon

[50] Miolo G, Marzano C, Gandin V, Palozzo A C, Dalzoppo D, Salvador A, Caffieri S (2011). Photoreactivity of 5-fluorouracil under UVB light: Photolysis and cytotoxicity studies. Chemical Research in Toxicology, 24(8): 1319–1326

[51] Mohamed H S, Dahy A A, Hassan G S, Eid S M, Mahfouz R M (2017). Quantum-chemical investigation on 5-fluorouracil anticancer drug. Structural Chemistry, 28(4): 1093–1109

[52] National Cancer Institute (2018). Cancer Statistics. 2018. Bethesda: National Cancer Institute

[53] Negreira N, de Alda M L, Barceló D (2014). Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain: filtration, occurrence, and environmental risk. Science of the Total Environment, 497–498: 68–77

[54] Negreira N, López de Alda M, Barceló D (2013). On-line solid phase extraction-liquid chromatography-tandem mass spectrometry for the determination of 17 cytostatics and metabolites in waste, surface and ground water samples. Journal of Chromatography. A, 1280: 64–74

[55] Nielsen U, Hastrup C, Klausen M M, Pedersen B M, Kristensen G H, Jansen J L C, Bak S N, Tuerk J (2013). Removal of APIs and bacteria from hospital wastewater by MBR plus O₃, O₃+H₂O₂, PAC or ClO₂. Water Science & Technology, 67(4): 854–862

[56] Oldenkamp R, Huijbregts M A J, Hollander A, Versporten A, Goossens H, Ragas A M J (2013). Spatially explicit prioritization of human antibiotics and antineoplastics in Europe. Environment International, 51: 13–26

[57] Parrella A, Lavorgna M, Criscuolo E, Russo C, Fiumano V, Isidori M (2014). Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans. Chemosphere, 115: 59–66

[58] Qian J, Li W, Zhang Y, Yun Y, Zhang Y (2014). Degradation of anticancer drug 5-fluorouracil by Fenton and oxalic-Fenton process. Environmental Chemistry, 33(7): 1229–1234 (in Chinese)

[59] Rey R P, Padron A S, Leon L G, Pozo M M, Baluja C (1999). Ozonation of cytostatics in water medium. Nitrogen bases. Ozone Science and Engineering, 21(1): 69–77

[60] Rosal R, Gonzalo M S, Boltes K, Letón P, Vaquero J J, García-Calvo E (2009). Identification of intermediates and assessment of ecotoxicity in the oxidation products generated during the ozonation of clofibric acid. Journal of Hazardous Materials, 172(2–3): 1061–1068

[61] Sonntag C V, Gunten U V, Sonntag C V, Gunten U V (2012). Chemistry of Ozone in Water and Wastewater Treatment: from Basic Principles to Applications. London: Iwa Publishing

[62] Straub J O (2009). Combined environmental risk assessment for 5-fluorouracil and capecitabine in Europe. Integrated Environmental Assessment and Management, 6(Suppl. 1): 540–566

[63] Tauxe-Wuersch A, De Alencastro L F, Grandjean D, Tarradellas J (2006). Trace determination of tamoxifen and 5-fluorouracil in hospital and urban wastewaters. International Journal of Environmental Analytical Chemistry, 86(7): 473–485

[64] Tekle-Röttering A, Reisz E, Jewell K S, Lutze H V, Ternes T A, Schmidt W, Schmidt T C (2016). Ozonation of pyridine and other N-heterocyclic aromatic compounds: Kinetics, stoichiometry, identification of products and elucidation of pathways. Water Research, 102: 582–593

[65] Theruvathu J A, Flyunt R, Aravindakumar C T, von Sonntag C (2001). Rate constants of ozone reactions with DNA, its constituents and related compounds. Journal of the Chemical Society, Perkin Transactions 2, 3: 269–274

[66] Ueda Y, Saito A, Fukuoka Y, Yamashiro Y, Ikeda Y, Taki H, Yasuda T, Saikawa I (1983). Interactions of beta-lactam antibiotics and antineoplastic agents. Antimicrobial Agents and Chemotherapy, 23(3): 374–378

[67] Valsania M C, Fasano F, Richardson S D, Vincenti M (2012). Investigation of the degradation of cresols in the treatments with ozone. Water Research, 46(8): 2795–2804

[68] Wei X, Chen J, Xie Q, Zhang S, Ge L, Qiao X (2013). Distinct photolytic mechanisms and products for different dissociation species of ciprofloxacin. Environmental Science & Technology, 47(9): 4284–4290

[69] Yin K, Deng L, Luo J, Crittenden J, Liu C, Wei Y, Wang L (2018). Destruction of phenicol antibiotics using the UV/H₂O₂ process: Kinetics, byproducts, toxicity evaluation and trichloromethane formation potential. Chemical Engineering Journal, 351: 867–877

[70] Yu X, Zuo J, Tang X, Li R, Li Z, Zhang F (2014). Toxicity evaluation of pharmaceutical wastewaters using the alga Scenedesmus obliquus and the bacterium Vibrio fischeri. Journal of Hazardous Materials, 266: 68–74

[71] Zhang G, Liu C, Chen L, Hang T, Song M (2015). Identification of related substances in capecitabine by LC-MS. Chinese Journal of New Drugs, 24(16): 1902–1910 (in Chinese)

[72] Zhang J, Chang V W, Giannis A, Wang J Y (2013). Removal of cytostatic drugs from aquatic environment: A review. Science of the Total Environment, 445–446: 281–298

[73] Zhang W, Zhou S, Sun J, Meng X, Luo J, Zhou D, Crittenden J (2018). Impact of chloride ions on UV/H₂O₂ and UV/persulfate advanced oxidation processes. Environmental Science & Technology, 52(13): 7380–7389

[74] Zhao Y, Yu G, Chen S, Zhang S, Wang B, Huang J, Deng S, Wang Y (2017). Ozonation of antidepressant fluoxetine and its metabolite product norfluoxetine: Kinetics, intermediates and toxicity. Chemical Engineering Journal, 316: 951–963

[75] Zounková R, Odráska P, Dolezalová L, Hilscherová K, Marsálek B, Bláha L (2007). Ecotoxicity and genotoxicity assessment of cytostatic pharmaceuticals. Environmental Toxicology and Chemistry, 26(10): 2208–2214

Acknowledgements

This work was supported by the Major Science and Technology Program for Water Pollution Control and Treatment in China (No. 2017ZX07202006), and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1261).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11783-019-1143-2 and is accessible for authorized users.

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