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

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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.

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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).

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Authors and Affiliations

  1. School of Environment, State Key Joint Laboratory of Environmental Simulation and Pollution Control (SKLESPC), Beijing Key Laboratory for Emerging Organic Contaminants Control, Tsinghua University, Beijing, 100084, China

    Siyu Chen, Lee Blaney, Ping Chen, Shanshan Deng, Yixiang Bao & Gang Yu

  2. Department of Chemical, Biochemical, and Environmental Engineering, University of Maryland Baltimore County, Baltimore, MD, 21250, USA

    Lee Blaney & Mamatha Hopanna

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  1. Siyu Chen
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  2. Lee Blaney
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  3. Ping Chen
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  7. Gang Yu
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Correspondence to Gang Yu.

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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.

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Chen, S., Blaney, L., Chen, P. et al. Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity. Front. Environ. Sci. Eng. 13, 59 (2019). https://doi.org/10.1007/s11783-019-1143-2

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