Biennial Report on Carcinogens

The disposition of 5-fluorouracil (FUra) was studied in 19 colorectal cancer patients dunrng treatment with FUra and high-dose leucovorin (LV) with or without interferon x2a (IFN-a). All received LV 200 mg mIover 2 h. then FUra 400 mg m-2 over 5 min then FUra 400 mgm ' over 22 h. repeated on day 2. on a 14 day cycle. Nine patients also received IFN-a 6 MU every 48 h, starting at least 2 weeks before the study. Series of 14 blood samples were assayed for FUra by reversed-phase high-performance liquid chromatography (HPLC). Minimum Akaike information criterion estimation was used to determine the simplest effective pharmacokinetic model. This consisted of a single compartment with first-order (linear) and Michaelis-Menten (non-linear) components to drug elimination. This model gave r' >0.98 in 19 20 data sets. With the Michaelis constant (K,,) set at 15;LM. values were derived for the volume of distribution (Vd). the maximum rate of non-linear elimination (V,,) and the first-order elimination rate constant (ki,). Mean (± s.d.) values in control (no IFN-a) patients were: Vd 10.4 (± 1.9) 1 m-'. V,,. 182 (± 59) .tmol 1' h-' and k1, 4.35 (± 0.58) h-'. No significant differences were detected in patients receiving IFN-a. in whom the equivalent mean values were Vd 10.0 (±0.9)lm-2. V,,. 141 (±27)nmollI'h-' and kl, 3.% (±0.5)h-'. Mean trapezoidal AUC0 _h was similar in the two groups (control patients 116 1M h. IFNpatients 125 lim h). No significant correlations with renal or hepatic function were detected. These results, while not inconsistent with previous reports of a reduced rate of FUra elimination at higher IFN-c doses. suggest that any clinical effect of this moderate dose of IFN-a on FUra toxicity or activity is due to modulation at target cells. not to pharmacokinetic interaction.