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: V03AF06
Folinic acid is the formyl derivative of tetrahydrofolic acid, i.e. the active form of folic acid. It is involved in various metabolic processes including purine synthesis, pyrimidine nucleotide synthesis and amino acid metabolism.
Folinic acid is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Folinic acid and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. Folinic acid also protects cells from the effects of folate antagonist by repletion of the reduced folate pool. Folinic 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.
5-Fluorouracil inhibits inter alia DNA synthesis by binding thymidilate synthetase. The combination of disodium folinate with 5-fluorouracil results in the formation of a stable ternary complex consisting of thymidilate synthetase, 5-fluorodeoxy-uridinemonophosphate and 5,10-methylenetetrahydrofolate.
This leads to an extended blockade of thymidilate synthetase with enhanced inhibition of DNA biosynthesis, resulting in increased cytotoxicity as compared to 5-fluorouracil monotherapy.
A pharmacokinetic study was performed to demonstrate the bioequivalence of disodium folinate in comparison with a licensed calcium folinate reference preparation. The bioequivalence criteria determined were fulfilled in respect of the pharmacokinetic parameters for D- and L-folinic acid and for the metabolite 5-methyltetrahydrofolic acid. Calcium folinate and disodium folinate solutions are bioequivalent.
The distribution volume of folinic acid is not known. With i.v. application, peak serum levels of the parent substance (D/L-formyltetrahydrofolic acid, folinic acid) are obtained after 10 minutes.
The active isomeric form 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 and occurs more quickly and more completely after oral application than after parenteral application.
The inactive isomeric form D-5-formyltetrahydrofolic acid is excreted virtually completely unchanged via the kidneys. The active isomeric form L-5-formyltetra-hydrofolic acid is in part excreted unchanged via the kidneys, but is predominantly metabolised to folic acid.
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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