LACK OF EFFECT OF INTERFERON ALPHA-2A UPON FLUOROURACIL PHARMACOKINETICS

The disposition of 5-fluorouracil (FUra) was studied in 19 colorectal cancer patients during treatment with FUra and high-dose leucovorin (LV) with or without interferon alpha 2a (IFN-alpha). All received LV 200 mg m(-2) over 2 h, then FUra 400 mg m(-2) over 5 min then FUra 400 mg m(-2) over 22 h, repeated on day 2, on a 14 day cycle. Nine patients also received IFN-alpha 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(2) > 0.98 in 19/20 data sets. With the Michaelis constant (K-M) set at 15 mu M, values were derived for the volume of distribution (V-d), the maximum rate of non-linear elimination (V-max) and the first-order elimination rate constant (k(l,e). Mean (+/-s.d.) values in control (no IFN-alpha) patients were: V-d 10.4 (+/-1.9) 1 m(-2) V-max 182 (+/-59) mu mol l(-1) h(-1) and k(l,e), 4.35 (+/-0.58) h(-1). No significant differences were detected in patients receiving IFN-alpha, in whom the equivalent mean values were V-d 10.0 (+/-0.9) l m(-2), V-max 141 (+/-27) pmol l(-1) h(-1) and k(l,e) 3.96 (+/-0.5) h(-1). Mean trapezoidal AUC(0-22h) was similar in the two groups (control patients 116 mu M h, IFN-alpha patients 125 mu M 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-alpha doses, suggest that any clinical effect of this moderate dose of IFN-alpha on FUra toxicity or activity is due to modulation at target cells, not to pharmacokinetic interaction.