Influence of interferon alfa-2b with or without folinic acid on pharmacokinetics of fluorouracil.

Interferon alfa has been demonstrated to enhance the effect of fluorouracil (5-FU) on human colon cancer cell lines as well as in clinical studies. By several authors interest in focussed on the question whether the interaction between these two agents is reflected by changes of 5-FU kinetics. In the present study the pharmacokinetic behavior of 5-FU was investigated in combination with interferon alfa (IFN-alpha-2b) and further after adding the second well-established biomodulating agent folinic acid (FA). Ten patients with advanced gastrointestinal cancer received 5-FU as a weekly bolus injection of 750 mg/m2, IFN-alpha-2b 5 million units three times per week subcutaneously and FA as a short time infusion at 200 mg/m2. 5-FU plasma levels were determined by high performance liquid chromatography as a baseline measurement on day 1 before starting IFN-alpha-2b. Analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN-alpha-2b injection, and finally after also adding FA immediately infused before 5-FU injection. Biomodulation of 5-FU by IFN-alpha-2b alone resulted in a significant alteration of 5-FU kinetic parameters as demonstrated by an increase of area under the curve by 80%, and of blood concentration (co) by 65%, and a decrease of total clearance at 50%. These data may partly explain the observed enhancement of antiproliferative and toxic effects of this combination. On the other hand, when FA was added to this schedule, no significant changes of 5-FU kinetics could be documented. Therefore the theoretical benefit of such a double modulation cannot be supported by our findings. Further preclinical and clinical investigations are required to define the role of a triple combination of 5-FU with IFN-alpha-2b and FA.