Chemical Stability and Human Plasma Pharmacokinetics of Reduced Folates

Abstract

The in vitro stability and plasma pharmacokinetics of 5,10-methylenetetrahydrofolic acid (CH₂FH₄), tetrahydrofolic acid (FH₄), 5-methyltetrahydrofolic acid (CH, FH₄), and 5-formyltetrahydrofolic acid (5-CHOFH₄) were studied in view of their potential usefulness in cancer chemotherapy. Analysis of reduced folates was done on a high-performance liquid chromatography (HPLC) system. The high sensitivity of FH₄ and CH₂FH₄ to oxidation can be circumvented by use of high concentrations of the folates, addition of ascorbate, and by thorough exclusion of atmospheric O₂. Intravenous injection of 200 mg FH₄ or CH₂FH₄ resulted in average peak concentrations of 69.2 ± 3.2 nmol/ml and 46.3 ± 2.6 nmol/ml, respectively. The plasma concentration curves support the concept that these highly oxygen-sensitive reduced folates can be reliably administered as pharmaceuticals to cancer patients through the use of a suitable air-occlusive system for their preparation and administration.