Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: agents for detoxification of anti-neoplastic treatments.
ATC-code: V03AF03.
Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential co-enzyme for the synthesis of nucleic acids.

Calcium folinate is frequently used for the reduction of the toxicity and the counteracting of the activity of folate antagonists like methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and are in competition for transport in the cells, through which the outflow of folate antagonist is stimulated. It also protects the cells from the effects of folate antagonists through repletion of the reduced folate pool. Calcium folinate functions as pre-reduced source of H4-folate, thus it can also bypass the blockage of folate antagonists and form a source for the various co-enzyme forms of folic acid.

Calcium folinate is also frequently used in the biochemical modulation of fluoropyridine (5-FU) for increasing the cytotoxic activity. 5-FU inhibits thymidylate synthase (TS) an essential enzyme involved in the biosynthesis of pyrimidine, and calcium folinate increases the inhibition of TS by increasing the intracellular folate pool, through which the complex 5-FU-TS is stabilised and the activity increased.

Finally calcium folinate can be administered intravenously for the prevention and the treatment of a folate deficiency if it cannot be prevented or corrected by the administration of folic acid via the oral route. This may be the case with a total parenteral nutrition and with severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia as a result of folic acid deficiency if an oral administration is not possible.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
After an intramuscular administration of the watery solution, the systemic availability is equivalent to an intravenous administration. Lower peak serum concentrations (Cmax) are reached though.

Leucovorin Lyophilized Powder for Solution for Injection,   25. 3. 2015, RH Metabolism
Calcium folinate is a racemic mixture in which the L-form (L-5-formyl tetrahydrofolate, L-5-formyl- THF) is the active enantiomer.
The most important metabolite of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is primarily produced in the liver and in the intestinal mucous membrane.

Distribution
The distribution volume of folinic acid is unknown.
Peak serum concentrations of the parent substance (D/L-5-formyl tetrahydrofolic acid, folinic acid) are reached 10 minutes after the intravenous administration.
The AUC for L-5-formyl-THF and 5-methyl-THF were resp. 28.4 ± 3.5 mg.min/l and 129 ± 112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentrations than the L-5- formyl tetrahydrofolate.

Elimination
The elimination half-life is resp. 32-35 minutes for the active L-form and 352-485 minutes for the inactive D-form.
The total terminal half-life of the active metabolites is approximately 6 hours (after intravenous and intramuscular administration).

Excretion
80-90% with the urine (5- and 10-formyl tetrahydrofolates inactive metabolites), 5-8% with the faeces.