Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: medac, Gesellschaft für klinische, Spezialpräparate mbH, Theaterstr. 6, 22880, Wedel, Germany
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment
ATC code: V03AF
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.
Disodium levofolinate is bioequivalent with calcium levofolinate as well as with the racemate disodium folinate with respect to plasma concentrations of levofolinic acid and the main, active metabolite, 5-methyltetrahydrofolic acid after intravenous administration of the same molar dose of the active isomer.
The protein binding of levofolinic acid is about 27%. The volume of distribution is about 17.5 litres.
The active isomeric form levofolinic acid (l-5-formyltetrahydrofolic acid) is quickly metabolised to 5-methyltetrahydrofolic acid in the liver. It is assumed that this conversion is not linked to the presence of dihydrofolate reductase.
About 20% of an intravenous dose is excreted as unchanged levofolinic acid in urine. The clearance for levofolinic acid is about 205 ml/min. After intravenous administration, the half-life of levofolinic acid and the active metabolite, 5-methyltetrahydrofolic acid, is 0.5 hours and 6.5 hours, respectively.
Toxicity tests on combined use with 5-fluorouracil have not been carried out.
No further information is available of relevance to the prescriber which is not already included in other relevant sections of the summary of product characteristics.
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