2010 Focal Points Complete Set: Clinical Modules for by American Academy of Ophthalmology

By American Academy of Ophthalmology

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All reduced folates have an S chirality at the 6 carbon of the tetrahydropterine ring and the natural and unnatural isomers of 5-formyl tetrahydrofolate are designated respectively as (6S)- and (6R)-N5_HCOH4PteGlul~. After being used for many years as a rescue agent following high doses of the antifolate methotrexate (MTX) 5, leucovorin is now also administered clinically in combination with 5-fluorouracil (5-FU) to enhance its antitumor activity, an effect dependent on the replenishment of intracellular folate pools by the reduced folate 6 ,7.

The formation of the 5,10 pools in plasma is really spectacular, it's enormous amounts of the compound that seem to get formed very quickly, 40% of the concentrations of leucovorin that you're pushing. Given the 5,10-methylene is a relatively minor component, intracellularly probably around 5%, and given this, Dr. Houghton and others have shown that even with high concentrations of leucovorin, the ability to expand that pool was 3 or 4-fold at most. How to explain that apparent discrepancy in such an enormous conversion preferably, relatively small conversions in the cells?

Et aI.. Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate. Br. J. Clin. Pharmac•• 28:289 (1989). G. Wflliam. et aI.. 10methylenetetrahydrofolates and tetrahydrofolates in human colon tumors, can. Conun.. 1:167 (1989). G. T. Doig. Tissue folate polyglutamate chainlength determination by electrophoresis as thymidylate synthase-fluorodeoxyuridylate tematy complexes. Methods EnzymoL. 122:313 (1986). G. Priest. C. Schmitz. MA Bunni. and RK. Stuart. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose administered orally and intravenously.

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