Sodium folinate

Chemical formula: C₂₀H₂₂N₇NaO₇  Molecular mass: 495.148 g/mol 

Mechanism of action

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.

Pharmacodynamic properties

Pharmacodynamic effects

Biochemical rationale for the methotrexate rescue therapy with disodium folinate

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.

Biochemical rationale for the combination of disodium folinate with 5-fluorouracil

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.

Pharmacokinetic properties

Absorption

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.

Distribution

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.

Biotransformation

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.

Elimination

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.

Preclinical safety data

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.

Related medicines

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.