Chemical formula: C₂₀H₂₃N₇O₇ Molecular mass: 473.439 g/mol PubChem compound: 135398559
Levofolinate is the pharmacologically active isomer of 5-formyltetrahydrofolic acid. Levofolinate does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilising folates as a source of “one carbon” moieties. Levofolinate is actively and passively transported across cell membranes.
Folinic acid is the formyl derivative of tetrahydrofolic acid i.e. the active form of folic acid. Levofolinic acid is the biologically active l-isomer of racemic folinic acid. It is involved in various metabolic processes including purine synthesis, pyrimidine nucleotide synthesis and amino acid metabolism.
Levofolinic acid is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Levofolinic acid and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduced folate pool. Levofolinic acid does not require reduction by the enzyme dihydrofolate reductase. Thus it serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage of the dihydrofolate reductase and provide a source for the various coenzyme forms of folic acid.
Fluorouracil can inhibit DNA synthesis by binding to the enzyme thymidylate synthetase. The combination of disodium levofolinate with 5-fluorouracil results in the formation of a stable ternary complex consisting of thymidylate synthetase, 5-fluorodeoxy-uridinemonophosphate and 5,10-methylenetetrahydrofolate. This leads to an extended blockade of thymidylate synthetase with enhanced inhibition of DNA biosynthesis, resulting in increased cytotoxicity as compared to 5-fluorouracil monotherapy.
When levofolinate is injected intravenously it is 100% bioavailable.
The pharmacokinetics of levofolinate after intravenous administration of a 15 mg dose were studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/ml. Serum levo-5-methyl-THF concentrations reached a mean peak of 275 ng/ml and the mean time to peak concentration was 0.9 hours. The mean half-life for total-THF and levo-5-methyl-THF was 5.1 and 6.8 hours respectively.
The distribution and plasma levels of levofolinate following intramuscular administration have not been established.
The distribution in tissue and body fluids and protein binding have not been determined.
In vivo, levofolinate is converted to levo-5-methyltetrahydrofolic acid (levo-5-methyl-THF), the primary circulating form of active reduced folate. Levofolinate and levo-5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.
Levofolinate and levo-5-methyl-THF are excreted renally.
Due to the inherent lack of levofolinate toxicity, the influence of impaired renal or hepatic function on levofolinate disposition was not evaluated.
The pre-clinical data raises no concerns for the clinical uses indicated.
Toxicity tests on combined use with 5-fluorouracil have not been carried out. No further information is available.
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