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Pharmacology: Pharmacological actions: Folinic acid is the formyl derivative of tetrahydrofolic acid which is a metabolite and active form of folic acid. Folinic acid as a co-factor participates in many metabolic reactions including purine synthesis, pyrimidine synthesis and amino acid conversion. It is effective in the treatment of megaloblastic anaemia caused by folic acid deficiency and is a potent antidote for both the haematopoietic and reticuloendothelial toxic effects of folic acid antagonists, e.g. methotrexate, pyrimethamine, trimethoprim. Folinic acid is used in cytotoxic therapy as an antidote to folic acid antagonists which block conversion of folic acid to tetrahydrofolate by binding enzyme dihydrofolate reductase. In some cancers, folinic acid enters and 'rescues' normal cells, in preference to tumor cells, from the toxic effects of folic acid antagonists, due to a difference in membrane transport mechanism. This principle is applied in high-dose methotrexate therapy with 'folinic acid rescue'.
Pharmacokinetics: Distribution: Following administration, folinic acid enters the general body pool of reduced folates. It has been reported that, following intravenous, intramuscular and oral administration, peak serum level of total reduced folates are achieved within a mean time of 10 minutes, 52 minutes and 1.7 hours, respectively. Peak levels of 5-formyl THF appear at 10 minutes and 28 minutes following intravenous and intramuscular administration respectively. Folate is concentrated in the cerebrospinal fluid and liver although distribution occurs to all body tissues. The bioavailability of an oral dose is almost the same as an equivalent intramuscular dose.
Metabolism: Calcium folinate is rapidly and extensively converted to 5-methyl tetrahydrofolate (an active metabolite) in vivo, with less extensive conversion resulting from parenteral, as opposed to oral administration.
Reduction in the levels of parent compound coincides with the appearance of the active metabolite 5-methyl THF, which becomes the major circulating form of the drug. Peak levels are observed at 1.5 and 2.8 hours following intravenous and intramuscular administration respectively. The terminal half-life for total reduced folates is reported as 6.2 hours. Tetrahydrofolic acid and its derivatives are distributed to all body tissues, being concentrated in the liver and found in moderate amounts in the CSF. Following a 15 mg dose given either orally or intramuscularly, peak serum folate concentrations of 0.268 micrograms/mL and 0.241 micrograms/mL were detected.
Excretion: Folinic acid is eliminated mainly as 10-formyl tetrahydrofolate and 5, 10-methyl tetrahydrofolate. The metabolites are mainly excreted via the urine (80-90%), with elimination being logarithmic in doses exceeding 1 mg.
