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. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability.Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria.Results:DPD activity in patients with mild toxicities (WHOgrade 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 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe 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 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity.Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.