Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage

Purpose: Patients with genetic fluorouracil (5-FU) catabolic deficiencies a re cit high risk for severe toxicity. To predict 5-FU catabolic deficiencie s and toxic side effects, we conducted a prospective study of Patients trea ted for advanced colorectal cancer by high-dose 5-FU, Patients and Methods: Eighty-one patients were treated with weekly infusion s of 5-FU and folinic acid, The initial 5-FU dose of 1,300 mg/m(2) was indi vidually adjusted according to ct dose-adjustment chart. Plasma concentrati ons of uracil (U) and its dihydrogenated metabolite, dihydrouracil(UH2), we re measured before treatment, and the ratio of UH2 to U was calculated. Pha rmacokinetic and pharmacodynamic studies were conducted to look for a relat ionship between the ratio of UH2 to U and 5-FU metabolic outcome and tolera nce. Results: The UH2-U ratios were normally distributed (mean value, 2.82; rang e, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r = .58), (2) 5-FU plasma clearance (r = .6 39), and (3) individual optimal therapeutic 5-FU dose (r = .65). Toxic side effects were observed only in patients with initial UH2-U ratios of less t han 1.8. No adverse effects were noted in patients with UH2-U ratios of gre ater than 2.25. Conclusion: The UH2-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of t oxicity. (C) 1999 by American Society of Clinical Oncology.