Pharmacokinetics of reduced folates after short-term infusion of d, 1-folinic acid.
After the use of d,1-folinic acid (d,1-CHO-THF), pharmacokinetic measurements should take into account 1-CHO-THF and its metabolite 1-methyltetrahydrofolic acid (1-CH3-THF) as well as d-CHO-THF. For this purpose, we developed a simple and rapid assay by combining reversed-phase HPLC to determine total levels of d,1-CHO-THF and CH3-THF and chiral HPLC to separate the biologically active 1-CHO-THF from the inactive d-CHO-THF. We investigated the pharmacokinetics after short-term infusion of 300 mg d,1-CHO-THF in ten healthy volunteers. With a mean of 56.5 min, 1-CHO-THF exhibits a rapid body clearance of 222 ml/min, about 60% of which is caused by metabolism to CH3-THF and 40%, by renal excretion. CH3-THF has a terminal half-life of 208 min and a total body clearance of 88.9 ml/min, which is essentially the same as the renal clearance. Due to the lower clearance of CH3-THF, its AUC (2,132 microM x min) exceeds that of 1-CHO-THF (1445 microM x min) by approximately 50%. In contrast to that of the reduced 1-folates, the total body and renal clearance of d-CHO-THF is very low, with values of 13.2 and 12.9 ml/min, respectively. This results in a very high AUC of 24, 269 microM x min, which is higher by factors of 17 and 11 than those of 1-CHO-THF and CH3-THF, respectively. The implications of the distinct kinetics of the reduced 1-folates and d-CHO-THF for the efficacy of folinic acid/5-fluorouracil therapy and adequate protocols for the treatment of advanced colorectal cancer are discussed.
Schalhorn
A
A
Medizinische Klinik III, Ludwig-Maximilians-Universität München, Federal Republic of Germany.
Kühl
M
M
Stupp-Poutot
G
G
Nüssler
V
V
D000328:Adult; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D002955:Leucovorin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013763:Tetrahydrofolates / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors
D013763:Tetrahydrofolates; D002955:Leucovorin; C005984:5-methyltetrahydrofolate