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

Abstract

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.

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

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature