Purpose: To detect possible interactions between (-)-formyl-tetrahydrofolic acid (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration.
Methods: Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (-)-fTHF and (+/-)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of (14)C-(-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure.
Results: The pharmacokinetic parameters obtained for (-)-fTHF following the administration of (-)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 microg. h/ml; maximum concentration, 12 microg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (+/-)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (-)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of (14)C-(-)-mTHF did not depend on the presence of (+)-mTHF at either concentration.
Conclusions: These data suggest that (-)-fTHF is not therapeutically superior to (+/-)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers.