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Front. Environ. Sci. Eng.    2019, Vol. 13 Issue (4) : 59    https://doi.org/10.1007/s11783-019-1143-2
RESEARCH ARTICLE
Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity
Siyu Chen1, Lee Blaney1,2, Ping Chen1, Shanshan Deng1, Mamatha Hopanna2, Yixiang Bao1, Gang Yu1()
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
2. Department of Chemical, Biochemical, and Environmental Engineering, University of Maryland Baltimore County, Baltimore, MD 21250, USA
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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.
Keywords Ozone      5-fluorouracil      Capecitabine      Hydroxyl radicals      Chemotherapy agents      Toxicity     
Corresponding Author(s): Gang Yu   
Issue Date: 01 July 2019
 Cite this article:   
Siyu Chen,Lee Blaney,Ping Chen, et al. Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity[J]. Front. Environ. Sci. Eng., 2019, 13(4): 59.
 URL:  
https://academic.hep.com.cn/fese/EN/10.1007/s11783-019-1143-2
https://academic.hep.com.cn/fese/EN/Y2019/V13/I4/59
Fig.1  Apparent second-order rate constants at 27°C±1°C for the reaction of aqueous ozone with 5-FU and CAP as a function of solution pH. The solid curves stem from Eq. (3) (5-FU) and (7) (CAP), and the dashed curves are 95% confidence bands.
Fig.2  (a) Normalized 5-FU and CAP concentrations as a function of ozonation time and (b) the contribution of hydroxyl radicals (f •OH) to transformation of 5-FU and CAP as a function of the overall 5-FU or CAP transformation for different inlet ozone gas concentrations (i.e., 2, 8, and 13 g O3/m3). The experimental conditions were as follows: temperature, 27°C±1°C; pH, 7 (10 mM phosphate buffer); initial pCBA concentration, 2.5 mM; and, initial AD concentration, 50 mM.
Fig.3  Fukui contour maps with isovalue of 0.01 for the following: (a) f?− for 5-FU; (b) f?0 for 5-FU; (c) f?− for 5-FU−; (d) f?0 for 5-FU−; (e) f?− for 5-FU2−; and, (f) f?0 for 5-FU2−. The Fukui function parameters f?− and f?0 correspond to electrophilic O3 attack and •OH attack, respectively.
Fig.4  Fukui contour maps with isovalue of 0.01 for the following parameters: (a) f?− for CAP; (b) f?0 for CAP; (c) f?− for CAP−; and, (d) f?0 for CAP−. The Fukui parameters f?− and f?0 correspond to electrophilic O3 attack and •OH attack, respectively.
Fig.5  Proposed reaction pathways for ozonation of (a) 5-FU and (b) CAP. Structures in the dashed boxes were confirmed by QTOF-MS.
Fig.6  Carboxylic acid and aldehyde concentrations during ozonation of (a) 5-FU and (b) CAP; fractional TOC contributions from ADs and other species for ozonation of (c) 5-FU and (d) CAP. The experimental conditions were as follows: inlet ozone gas concentration, 8 g O3/m3; temperature, 27°C±1°C; pH, 7 (10 mM phosphate buffer); and, initial concentration of parent compound, 50 mM. Acetone-DNPH and acrolein-DNPH had the same retention time and could not be separated. The color of the legend entries for (a) and (b) are also used in (c) and (d). The TOC removal for these experiments is plotted in Fig. S5 of the SI.
Fig.7  (a) 15-min luminescence inhibition of V. fischeri for ozonated 5-FU and CAP solutions; (b) predicted 48-h LC50 for D. magna of CAP and its transformation products using the consensus method in the TEST software. Conditions for (a) were as follows: inlet ozone gas concentration, 8 g O3/m3; temperature, 27°C±1°C; pH, 7 (10 mM phosphate buffer); and, initial concentration of parent compound, 50 mM.
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https://doi.org/10.1897/07-137R.1 pmid: 17867890
[1] FSE-19050-OF-CSY_suppl_1 Download
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