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Pharmacokinetic interaction of 5-fluorouracil and interferon alpha-2b with or without folinic acid

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Abstract

The purpose of this study was to evaluate a potential pharmacokinetic (PK) interaction between fluorouracil (5-FU) and the biomodulating agent interferon alpha (IFN-α) in patients with metastatic colorectal carcinoma. 5-FU was applied as an intravenous bolus injection of 750 mg m−2 weekly and IFN-α 2b (IFN) 5 MU was injected 3 times weekly (TIW) subcutaneously. In the first study, 13 patients were treated by this schedule, 5-FU plasma levels were determined by HPLC on day (d) one as baseline before starting IFN; the analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN injection respectively. In the second study, 10 patients additionally received folinic acid (FA) 200 mg m−2 as a short time infusion immediately before 5-FU, and a third analysis of FU kinetics was performed in order to compare the influence of a double modulation of IFN and FA to IFN alone. Combination of 5-FU and IFN resulted in a significant increase of the AUC of 5-FU (80%) and the fictive initial concentration (C0, 65%) obviously caused by a reduction of 5-FU clearance by 50%. However, when FA was added to this schedule, no significant changes of FU kinetics compared to 5-FU alone could be documented. Finally, in two pilot patients 5-FU 750 mg was given as a continuous infusion (CI) over 5 days and IFN 5 × 106 u was added daily from d2 to d5. Analysis of 5-FU plasma levels was performed over 24 hours on d1 as baseline, on d2 after the first IFN injection and on d5 after the 4th IFN application. Compared to 5-FU alone, already on d2 there was a slight, but on d5 a marked increase of 5-FU plasma levels. This PK effect may contribute to the cytostatic action of 5-FU combined with IFN, especially in patients with enhanced 5-FU catabolism. Abrogation of this effect by using a double modulation of IFN and FA must be considered as disadvantageous despite several theoretical and preclinical synergism.

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  1. Department of Oncology, Hospital Rudolfstiftung, Juchgasse 25, A-1030, Vienna, Austria

    Johannes Schüller

  2. Institute for Pharmaceutical Chemistry, University of Vienna, Austria

    Martin Czejka

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Schüller, J., Czejka, M. Pharmacokinetic interaction of 5-fluorouracil and interferon alpha-2b with or without folinic acid. Med Oncol 12, 47–53 (1995). https://doi.org/10.1007/BF01571408

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