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JNCI Journal of the National Cancer Institute 1991 83(24):1806-1812; doi:10.1093/jnci/83.24.1806
© 1991 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 83, No. 24, 1806-1812, December 18, 1991
© 1991 Oxford University Press

Pharmacokinetics of Leucovorin Metabolites in Human Plasma as a Function of Dose Administrated Orally and Intravenously

David G. Priest*,, John C. Schmitz, Marlene A. Bunni, Robert K. stuart

Department of Biochemistry and Molecular Biology, Medical University of South Carolina Charleston
Department of Medicine, Medical University of South Carolina Charleston

*Correspondence to: David G.Priest, Ph.D., Department of Biochemistry and Molecular Biology Medical University of South Carolina 171 Ashley Ave., Charteston, SC 29425-221.

Studies have shown that conversion of leucovorin to the metabolite 5,10-methylenetetrahydrofolate (5,10-CH2FH4) is responsible for enhancement of the antitumor effects of fluorouracil given in combination with leucovorin, but the biochemical basis of this conversion in humans is not fully understood. To determine a possible sequence of metabolic steps, we studied the pharmacokinetics of leucovorin and its reduced folate metabolites in plasma in healthy volunteers. Groups of five subjects were given two equal doses of 10, 25, 125, 250, or 500 mg/m2 leucovorin, one orally and one intravenously at a 30-day interval. A sensitive radioenzymatic method that we developed previously was used to measure plasma concentrations of [S]5-formyltetrahydrofolate, 10-formyltetrahydrofolate (10-CHOFH4), 5-methyltetrahydro-folate (5-CH3FH4), and the combined 5,10-CH2FH4 + tetrahydrofolate (FH4) pools. Intravenous administration of leucovorin resulted in dose-dependent accumulation of 5,10-CH2FH4 + FH4 exceeding 2µM at peak levels. After oral and intravenous administration, 10-CHOFH4 and 5,10-CH2FH4+ FH4 exhibited peak levels earlier and were eliminated more rapidly than 5-CH3FH4. Accumulation of all metabolites after intravenous administration was linearly dose dependent, while oral administration appeared to result in saturation. We propose that the host activation of leucovorin suggested by these findings could be responsible for elevation of intratumor 5,10-CH2FH4 levels, thus enhancing the antitumor effects of fluorouracil. These results also suggest that 10-CHOFH4, 5,10-CH2FH4, and FH4 are intermediate metabolites and that 5-CH3FH4 is the terminal metabolite. In addition, our results indicate that attainment of high plasma levels of the metabolites active in modulation of the therapeutic effects of fluorouracil is best achieved through intravenous administration of high doses of leucovorin. Our future studies will address the proposed sequential conversion pathway and, thus, the mechanism by which pharmacologically relevant reduced folates accumulate in plasma after leucovorin administration.


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