Disposition of leucovorin and its metabolites in dietary folic acid-deplete mice – comparison between tumor, liver and plasma

Purpose: A comprehensive pharmacokinetic study of leucovorin (5-formyltetrahydrofolate, 5-HCO-FH₄) and its metabolites was conducted in plasma, liver and implanted tumor tissue from mice maintained on a low folic acid diet. While it has been previously demonstrated that the antitumor activity of fluorouracil (FU) can be potentiated by 5-HCO-FH₄, the optimum time for administration of FU after 5-HCO-FH₄, to maximally elevate the active folate metabolite methylenetetrahydrofolate in tumor has not been established. Human plasma studies have defined the pharmacokinetics of circulating 5-HCO-FH₄ and its metabolites, but comparison with human tumor accumulation has not been practicable because of sampling difficulties. As an alternative, a mouse model system, based on low dietary folic acid, was used to evaluate plasma, liver and implanted tumor reduced folates after administration of 5-HCO-FH₄.Methods: Plasma and tissue samples were collected from folate-deplete mice over a 12-h period after intraperitoneal administration of 90 mg/kg R, S ] 5-HCO-FH₄. Reduced folates were evaluated using a ternary complex assay. Results: The time at which max‐imal accumulation of parent compound and all metabolites, except 5-methyltetrahydrofolate (5-CH₃FH₄), occurred in tumor was the same as in plasma. Alternatively, peak liver accumulation was delayed relative to plasma for all folates except 5-CH₃FH₄. Conclusions: The results suggest that mouse plasma accumulation of reduced folates, with the exception of 5-CH₃FH₄, can predict tumor accumulation. Hence, evaluation of human plasma folate accumulation may potentially provide a means to improve the timing of the administration of FU relative to 5-HCO-FH₄ to achieve a superior therapeutic outcome. Received: 24 July 1996 / Accepted: 29 October 1996