Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background: Previous work demonstrated that 5-fluorouracil (5-FU) metabolism is a critical factor for treatment tolerability. In order to study the predictivity of pharmacokinetics with respect to the occurrence of 5-FU toxicity, this study investigates the relationship between the pharmacokinetics of 5-FU and its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMNC) and treatment tolerability. Patients and methods: Pharmacokinetics and metabolism of 5-FU and activity of DPD in PBMNC were examined in 110 colorectal cancer patients given adjuvant 5-FU 370 mg/m2 plus L-folinic acid 100 mg/m2 for five days every four weeks. Drug levels were examined by HPLC, while toxicities were graded according to WHO criteria. Results: DPD activity in patients with mild toxicities (WHO grade ≤ 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein, while in five patients with grade 3-4 gastrointestinal toxicity, DPD ranged from low to normal values (range 31.12-182.37 pmol/min/mg of protein). In these patients, 5-FU clearance (CL) was lower (range 14.12-25.17 l/h/m2), and the area under the curve (AUC) was higher (range 14.70-26.20 h × μg/ml) than those observed in 84 patients with mild toxicities (CL, 56.30 ± 3.60 l/h/m2; AUC, 7.91 ± 0.44 h × μg/ml). The severity of adverse events was associated with increased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and 5-FDHU pharmacokinetics were not related to DPD activity. Conclusion: This study shows that DPD activity in PBMNC is unrelated to 5-FU/5-FDHU disposition and patients with severe toxicity display marked pharmacokinetic alterations while a reduction of DPD activity may not occur.