Impact of the simultaneous administration of the (+)- and (-)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (-)-tetrahydrofolic acid

Purpose: To detect possible interactions between (-)-formyl-tetrahydrofolic acid (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultane ous administration. Methods: Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the adm inistration of both (-)-fTHF and (+/-)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intra cellular uptake of C-14-(-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highl y specific high-performance liquid chromatography procedure. Results: The p harmacokinetic parameters obtained for (-)-fTHF following the administratio n of (-)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 1 0 mu g.h/ml; maximum concentration, 12 mu g/ml; clearance, 305 ml/min; volu me of distribution, 19 l. The parameters did not differ significantly as co mpared with those obtained following the administration of (+/-)-fTHF to bo th volunteers and patients. There were no differences in the pharmacokineti cs of (-)-mTHF or in the protein binding of both substances with the differ ent forms of administration. The intracellular uptake of C-14- (-)-mTHF did not depend on the presence of (+)-mTHF at either concentration. Conclusion s: These data suggest that (-)-fTHF is not therapeutically superior to (+/- )-fTHF and that the latter is appropriate during combination chemotherapy w ith 5-FU/fTHF in patients with colorectal cancers.