Chemical formula: C₂₀H₂₁N₇Na₂O₇ Molecular mass: 517.13 g/mol
Sodium levofolinate is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Sodium levofolinate does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
Sodium levofolinate enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Sodium levofolinate is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which then acts to stabilize the binding of FdUMP to thymidylate synthase, thereby enhancing the inhibition of thymidylate synthase.
The pharmacokinetics of sodium levofolinate after intravenous injection of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentration was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentration was 275 ng/mL (CV 18%) observed around 0.9 hours post injection.
Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.
The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate.
The mean dose-normalized steady-state plasma concentrations for both sodium levofolinate and 5-methyl-THF were comparable whether fluorouracil (370 mg/m2/day as an intravenous bolus) was given in combination with sodium levofolinate (250 mg/m2 and 1000 mg/m2 as a continuous intravenous infusion for 5.5 days) or in combination with d,l-leucovorin (500 mg/m2 as a continuous intravenous infusion for 5.5 days).
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