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Pharmacokinetics of reduced folates after short-term infusion of d, 1-folinic acid.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 1990; Vol. 25 (6), pp. 440-4. - Publication Year :
- 1990
-
Abstract
- 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.
- Subjects :
- Adult
Chromatography, High Pressure Liquid methods
Female
Half-Life
Humans
Infusions, Intravenous
Kidney metabolism
Leucovorin administration & dosage
Leucovorin metabolism
Male
Metabolic Clearance Rate
Molecular Conformation
Oxidation-Reduction
Tetrahydrofolates metabolism
Time Factors
Leucovorin pharmacokinetics
Tetrahydrofolates pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0344-5704
- Volume :
- 25
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 2311173
- Full Text :
- https://doi.org/10.1007/BF00686056