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-methyl-tetrahydrofolate (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 50mg. The aim of this study was to assess whether 5 oral doses of (6S)-LV 50mg 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 50mg 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 50mg, 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 50mg, 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).