Clinical pharmacology of the stereoisomers of leucovorin during repeated oral dosing.

As part of a clinical trial of cisplatin, 5-fluorouracil (5-FU), and leucovorin (LV) for treatment of patients with advanced head and neck cancer, patients received 100 mg of LV (d,l-5-formyltetrahydrofolate) orally every 4 hours for 5 days. On days 2 and 4 of treatment, plasma samples were obtained 2 hours after (peak) and 30 minutes before (trough) a dose of LV. Total LV and 5-methyltetrahydrofolate (THF) concentrations were measured with high-performance liquid chromatography (HPLC) analysis. LV stereoisomer concentrations were determined by chiral HPLC on a bovine serum albumin-bonded silica column. Thus far, plasma folate levels have been analyzed for ten cycles of treatment administered to 7 patients (40 samples). Administration of LV in divided oral doses approximates a plasma steady state with no significant differences noted between peak and trough concentrations. Mean (+/- SD) plasma concentrations for all samples were (mumol): LV, 3.2 +/- 1.3; l-LV, 0.28 +/- 0.21; d-LV, 2.9 +/- 1.2; and THF, 4.25 +/- 2.5. Plasma levels of d-LV and THF tended to be approximately 10% higher on day 4 than day 2, although mean differences were not significantly different due to substantial interpatient variability. Of note was that the sum of THF and l-LV exceeds that of d-LV which was consistent with selective absorption of the l-isomer of LV. Mean ratios of d-LV/l-LV and d-LV/l-LV and THF were 13.7 +/- 10 and 0.88 +/- 0.68, respectively. The authors conclude that oral administration of LV in divided dose (1) simulates a continuous intravenous infusion; (2) produces plasma levels of l-reduced folates in a range known to potentiate 5-FU cytotoxicity; and (3) results in low ratios of d/l-reduced folates that may be important in maximizing the effectiveness of 5-FU-LV chemotherapy.