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Correlation between pharmacokinetic parameters of 5-fluorouracil and related metabolites and adverse reactions in East-Asian patients with advanced colorectal cancer

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Abstract

Background and objective

To examine the range of the area under the concentration–time curve (AUC) calculated using plasma 5-FU concentration at steady-state plasma concentration–time of 5-fluorouracil (5-FU) and correlation between 5-FU metabolites (5,6-dihydro-5-fluorouracil, 5-FUH2 and α-fluoro-β-Alanine, FBAL) plasma concentration and adverse reactions when patients with advanced colorectal cancer (CRC) received 5-FU-based chemotherapy.

Methods

74 patients with advanced CRC receiving 5-FU-based chemotherapy from Aug. 2017 to Nov. 2020 in Harbin Medical University Cancer Hospital were involved in this study, the dosage of 5-FU being determined according to the patient's body surface area (BSA). Using an ultra-high performance liquid chromatography–tandem mass spectrum (UPLC–MS/MS) to determine the 5-FU steady-state plasma concentration (CSS) and plasma concentration of 5-FUH2 and FBAL in CRC patients receiving 5-FU in continuous intravenous infusion for 18–30 h, the start time and end time of 5-FU infusion in patients were accurately recorded and the continuous infusion time (TCI) was calculated. The AUC value was calculated according to AUC = CSS × TCI. At the same time, the treatment effects and adverse drug reactions of patients were evaluated, to analyze the relationship between 5-FU AUC, 5-FUH2 and FBAL plasma concentration and clinical efficacy and adverse reactions in CRC patients, and explore the ideal AUC range of 5-FU in the treatment of colorectal cancer.

Results

The AUC of 5-FU was not normally distributed and ranged from 3.13 to 41.12mgh/L, with an average value of 14.81 ± 8.62 mg·h /L, and the AUC values had obvious inter-individual differences up to 13 times. 5-FUH2 ranged from 131.98 to 987.93 ng/mL, with an average of 550.58 ± 260.60 ng/mL; FBAL ranged from 23.58 to 262.48 ng/mL, with an average of 89.79 ± 58.47 ng/mL. Correlation analysis results revealed a significant correlation between 5-FU AUC, 5-FUH2 and FABL plasma concentration and adverse reactions, 5-FU AUC and clinical efficacy.

Conclusions

There are obvious individual differences in AUC values in CRC patients receiving different dosages of 5-FU based on BSA. The ideal AUC range of 5-FU is 18.23–29.17 mg·h/L. There was a significant correlation between 5-FUH2 and FABL plasma concentration and adverse reactions.

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Funding

This study was supported by The Key Program of Harbin Medical University Cancer Hospital Haiyan Fund (no. JJZD2019-03) and The General Program of Harbin Medical University Cancer Hospital Haiyan Fund (no. JJMS2021-25). We are grateful to the patients and their families for their participation in this study.

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Author notes

  1. Zhiqiang Tong, Mengfei Cheng and Yang Yu have contributed equally.

Authors and Affiliations

  1. Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China

    Zhiqiang Tong, Mengfei Cheng, Yang Yu, Jiahui Liu, Shuo Zhang, Shuai Jiang & Mei Dong

  2. College of Pharmacy, Jiamusi University, Jiamusi, China

    Jiuhang Yu, Yichuang Yin & Mei Dong

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  1. Zhiqiang Tong
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  2. Mengfei Cheng
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Correspondence to Shuai Jiang or Mei Dong.

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Zhiqiang Tong, Mengfei Cheng, Yang Yu, Jiuhang Yu, Yichuang Yin, Jiahui Liu, Shuo Zhang, Shuai Jiang and Mei Dong declare that they have no commercial or associative interests that represent a conflict of interest in connection with the work submitted.

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Tong, Z., Cheng, M., Yu, Y. et al. Correlation between pharmacokinetic parameters of 5-fluorouracil and related metabolites and adverse reactions in East-Asian patients with advanced colorectal cancer. Cancer Chemother Pharmacol 89, 323–330 (2022). https://doi.org/10.1007/s00280-021-04387-y

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