Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil: a case report

Objective: To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman affected by a severe 5-FU toxicity. Methods: Toxicities were rated according to World Health Organization. 5-FU and 5-FDHU plasma concentrations and dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear cells (PBMC) were measured by HPLC analysis. Results: After a single cycle of 5-FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3 vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU AUC, elimination half-life, and Cmax were markedly increased (24.75 vs. 9.25±0.63) h μg/ml, >5 vs. 0.36±0.05 h, and 58.54 vs. 37.2±4.03 μg/ml, respectively) whereas systemic clearance was decreased (12 vs. 51.29±2.97 l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35±0.7 hμg/ml) and Cmax (3.4 vs. 4.56±0.15 μg/ml), which was reached with delay, were reduced. Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary uracil (68.32 μmol/g urinary creatinine) were within normal range. Conclusions: Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and suggest the necessity of a pharmacological evaluation of 5-FU treated patients.