An in vitro approach to simulate the process of 5-fluorouracil degradation with dihydropyrimidine dehydrogenase: the process in accordance to the first-order kinetic reaction

Abstract

1. Partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) has been observed in 3%–5% and 0.1% of the general population, respectively. It causes severe toxicity in the context of 5-fluorouracil (5-FU) therapy. However, the current tests for determination of DPD deficiency have limitations in routine clinical usage.

2. Therefore, an in vitro approach for simulating 5-FU degradation was established by mixing 5-FU with blank whole blood matrix in this study. The effects of initial 5-FU concentrations and temperatures on DPD activities were investigated as well.

3. The degradation process followed the first-order kinetic reaction (r² > 0.98). The degradation rates were determined by temperature and individually different. The DPD inhibitor, gimeracil, could block this degradation, which indicated that DPD was the main factor. The degradation process of 5-FU in patients’ whole blood in vitro was consistent with it after mixing 5-FU with blank whole blood matrix.

4. In conclusion, mixing 5-FU with blank matrix can simulate the process of 5-FU degradation with DPD.

Keywords:

• 5-Fluorouracil
• UPLC-MS/MS
• degradation
• dihydropyrimidine dehydrogenase
• gimeracil
• first-order kinetic reaction

Acknowledgements

The authors thank Professor Fei Shang from Beijing University of Chemical Technology for his kindly help in establishing UPLC-MS/MS method and pharmacist Xiaoyuan Liu from Affiliated Hospital of Jiangnan University for the sample preservation solution. The authors also thank LetPub and Zhuofei Cheng for its linguistic assistance during the preparation of this manuscript.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by the Natural Science Foundation of China for financial [grant numbers: 81903719], the Fundamental Research Funds for the Central Universities [grant numbers: 3332019116] and the scientific research project of China-Japan friendship hospital [grant numbers: 2018-2-QN-29].