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

Abstract

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. 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 18-30h, 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. 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 ± 8.62mg·h /L, and the AUC values had obvious inter-individual differences up to 13 times. 5-FUH2 ranged from 131.98 to 987.93ng/mL, with an average of 550.58 ± 260.60ng/mL; FBAL ranged from 23.58 to 262.48ng/mL, with an average of 89.79 ± 58.47ng/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. 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 18.23-29.17mg·h/L. There was a significant correlation between 5-FUH2 and FABL plasma concentration and adverse reactions.