Litacor Mechanism of Action

Pharmacology: Pharmacodynamics: Leucovorin is a derivative of tetrahydrofolic acid, the reduced form of folic acid, which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purines and pyrimidines of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists (e.g., methotrexate, pyrimethamine, trimethoprim). It is postulated that in some cancers leucovorin enters and "rescues" normal cells from the toxic effects of folic acid antagonists, in preference to tumor cells, because of a difference in membrane transport mechanisms; this principle is the basis of high-dose methotrexate therapy with "leucovorin rescue."
Pharmacokinetics: In vivo, leucovorin calcium is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body. Following oral administration of a 15 mg (7.5 mg/m²) dose in healthy men, mean peak serum folate concentrations of 268 μg/mL occur within about 1.72 hours.
Tetrahdyrofolic acid and its derivatives are distributed to all body tissues; the liver contains about one-half of total body folate stores. In a small number of patients, biliary concentrations of folate was about 4.5 times the plasma folate concentration after oral administration of a 2 mg dose of leucovorin; this is believed to represent the hepatic folate pool rather than excretion of the administered dose.
Leucovorin is excreted in urine, mainly as 10-formyl tetrahydrofolate and 5,10-methenyl tetrahydrofolate. There is some evidence that 5-methyl tetrahydrofolate may be conserved by the kidneys in preference to 5-formyl tetrahydrofolate (leucovorin). Loss of folate in the urine becomes approximately logarithmic as the amount of leucovorin administered exceeds 1 mg.