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.
Czejka
M J
MJ
Department of Clinical Pharmacy, University of Vienna, Austria.
Schüller
J
J
Weiss
C
C
Bandak
S
S
Meyer
B
B
Simon
D
D
D000368:Aged; D000704:Analysis of Variance; D000931:Antidotes / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D001682:Biological Availability; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics*; D002955:Leucovorin / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins; D013763:Tetrahydrofolates / Q000097:blood*
D000931:Antidotes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013763:Tetrahydrofolates; D002955:Leucovorin; D005472:Fluorouracil