Disposition of leucovorin and its metabolites in dietary folic acid-deplete mice - comparison between tumor, liver, and plasma.
OBJECTIVE
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 maximal 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.
Raghunathan
K
K
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Schmitz
J C
JC
Priest
D G
DG
D000818:Animals; D019731:Carbon-Nitrogen Ligases; D004357:Drug Synergism; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000378:metabolism*; D002955:Leucovorin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008025:Ligases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000378:metabolism*
D005492:Folic Acid; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase; D002955:Leucovorin