CHEMICAL-STABILITY AND HUMAN PLASMA PHARMACOKINETICS OF REDUCED FOLATES

The in vitro stability and plasma pharmacokinetics of 5, 10-methylenet etrahydrofolic acid (CH2FH4), trtmhydrofolic acid (FH4), 5-methyltetra hydrofolic acid (CH3FH4), and 5-formyltetrahydrofolic acid (5-CHOFH4) were studied in view of their-potential usefulness in cancer chemother apy. Analysis of reduced folates was done on a high performance liquid chromatography (HPLC) system. The high sensitivity of FH4 and CH2FH4 to oxidation call be circumvented by use of high concentrations of the folates, addition of ascorbate, and by thorough exclusion of atmosphe ric O-2. Intravenous injection of 200 mg FH4 or CH2FH4 resulted in ave rage 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 ad ministered as pharmaceuticals to cancer patients through the use of a suitable air-occlusive system for their preparation and administration .