Pharmacokinetics of (6S)-leucovorin and 5-methyltetrahydrofolate after 4-hour continuous intravenous infusion followed by repeated oral doses of (6S)-leucovorin in patients with colorectal cancer treated with 5-fluorouracil

As part of a clinical trial of 5-fluorouracil (5-FU) administered as a 24-hour intravenous infusion in patients with colorectal carcinoma, pharmacokinetic studies of (6S)-leucovorin [(6S)-LV] and its major metabolite 5-methyltetrahydrofolate (5-CH₃-THF) were performed in 8 patients given a continuous intravenous infusion of(6S)-LV 100 mg/m² followed by 5 oral doses of (6S)-LV 50 mg. The aim of this study was to assess whether 5 oral doses of (6S)-LV 50 mg administered after intravenous treatment can maintain the plasma concentrations of reduced folates within the range shown to optimise 5-FU cytotoxicity throughout a 24-hour period of 5-FU treatment. The pharmacokinetics of (6S)-LV 50 mg administered orally was investigated in 4 additional patients. The mean (± SD) plasma concentrations of (6S)-LV and 5-CH₃-THF after 4-hour infusion of (6S)-LV, before 5-FU treatment, were 14.5 ± 3.1 μmol/L and 4.7 ± 2.8 μmol/L, respectively; at 4 hours postinfusion, before starting repeated oral doses, their concentrations were 1.2 ± 0.5 μmol/L and 3.6 ± 1.4 μmol/L, respectively. At 4 hours after a single oral dose of (6S)-LV 50 mg, the mean plasma concentrations of (6S)-LV and 5-CH₃-THF were 0.4 ± 0.2 μmol/L and 2.7 ± 1.0 μmol/L. (6S)-LV was cleared from plasma more slowly after oral [mean residence time (MRT) = 2.1 ± 0.2 hours] than after intravenous treatment (MRT = 1.5 ± 0.5 hours). At the end of 5-FU treatment, after 5 oral doses of (6S)-LV 50 mg, the mean plasma concentrations of total reduced folates [(6S)-LV + 5-CH₃-THF] were in the range reported for the synergism with fluoropyrimidines after either intravenous (3.1 ± 0.9 μmol/L) or oral treatment (2.7 ± 0.6 μmol/L). The present study suggests that a regimen combining a 4-hour continuous infusion followed by repeated oral doses of (6S)-LV is able to maintain modulating plasma concentrations of total bioactive folates throughout a 24-hour continuous infusion of 5-FU.