Disposition of 5-formyl- and 5-methyltetrahydrofolic acid in serum after i.v. bolus of calcium folinate: pharmacokinetic drug interaction with preadministered interferon-alpha-2b.

The influence of interferon (IFN) coadministered subcutaneously with the biomodulating agent folinic acid on the blood serum levels of 5-formyl-tetrahydrofolic acid (CHO-THFA) and the biotransformation into its main metabolite in the blood 5-methyltetrahydrofolic acid (CH3-THFA) was studied in patients receiving a chemotherapy with 5-fluorouracil. IFN causes a clear decrease of the serum concentrations of CHO-THFA and a statistically significant decrease of CH3-THFA concentrations (P < 0.01). The effect on serum concentrations could be observed in each patient, but in a different order of magnitude. As a consequence, the preadministration of IFN leads to a significant change in the basic pharmacokinetic parameters of both compounds: the mean area under the concentration-time curve is decreased at 27.4% for CHO-THFA (P < 0.025) and at 22.4% for CH3-THFA (P < 0.025), respectively. The total body clearance is elevated at 45.4% for CHO-THFA (P < 0.05) and at 23.4% for CH3-THFA (P < 0.05). The mean volume of distribution is increased by IFN at 38.2% for CHO-THFA (P < 0.025) and at 22.3% for CH3-THFA (P < 0.05). The nearly identical mean residence time in both groups indicates that CHO-THFA elimination is not affected by IFN. But the results prove a certain interaction between IFN and CHO-THFA. IFN accelerates the distribution of CHO-THFA as well as of its main metabolite from the blood into the tissue or activates the biotransformation of CHO-THFA into CH3-THFA inside the cells of the tissue. The extent of biotransformation of CHO-THFA into CH3-THFA, which takes place in the blood, is not influenced by IFN because percentage AUC-ratios CHO-THFA:CH3-THFA were 89.5:10.5% for the control group and 88.8:11.2% for the IFN group.