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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.
Xenobiotica ( IF 1.8 ) Pub Date : 2020-07-27 , DOI: 10.1080/00498254.2020.1799451
Wei Qin 1 , Xiaoxue Wang 1 , Wenqian Chen 1 , Wenwen Du 1 , Dan Zhang 1 , Xianglin Zhang 1 , Pengmei Li 1
Affiliation  

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.



中文翻译:

一种模拟二氢嘧啶脱氢酶降解5-氟尿嘧啶的过程的体外方法:该过程与一级动力学反应一致。

摘要

  1. 二氢嘧啶脱氢酶(DPD)的部分或完全缺乏分别在总人口中占3%–5%和0.1%。在5-氟尿嘧啶(5-FU)治疗的情况下会引起严重的毒性。但是,当前用于确定DPD缺乏症的测试在常规临床使用中存在局限性。

  2. 因此,在这项研究中,通过将5-FU与空白全血基质混合,建立了一种模拟5-FU降解的体外方法。还研究了初始5-FU浓度和温度对DPD活性的影响。

  3. 降解过程遵循一级动力学反应(r 2  > 0.98)。降解速率由温度决定,且各不相同。DPD抑制剂吉美拉西可以阻止这种降解,这表明DPD是主要因素。将5-FU与空白全血基质混合后,患者全血5-FU的降解过程与之一致。

  4. 总之,将5-FU与空白基质混合可以模拟DPD降解5-FU的过程。

更新日期:2020-07-27
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