Folinic acid
Encyclopedia
Folinic acid or leucovorin (USAN
), generally administered as calcium or sodium folinate (or leucovorin calcium/sodium), is an adjuvant
used in cancer
chemotherapy
involving the drug methotrexate
. It is also used in synergistic
combination with the chemotherapy agent 5-fluorouracil.
Levofolinic acid and its salts are the enantiopure drug
s. They are configurated S at the remaining asymmetric carbon atom (see below).
Folinic acid should be distinguished from folic acid
.
. It is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate), and, thus, has vitamin activity that is equivalent to that of folic acid. However, since it does not require the action of dihydrofolate reductase
for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate.
Folinic acid, therefore, allows for some purine
/pyrimidine
synthesis to occur in the presence of dihydrofolate reductase inhibition, so that some normal DNA
replication and RNA
transcription processes can proceed.
as part of a total chemotherapeutic plan, where it may "rescue" bone marrow
and gastrointestinal mucosa cells from methotrexate. There is no apparent effect on preexisting methotrexate-induced nephrotoxicity
.
While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be re-dosed until the methotrexate level is less than 5 x 10−8 M
Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase
.
Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial
dihydrofolate reductase inhibitors such as trimethoprim
and pyrimethamine
. Folinic acid may be prescribed in the treatment of toxoplasmosis
retinitis, in combination with the folic acid antagonists pyrimethamine
and sulfadiazine
.
Folinic acid has dextro- and levo-isomers, only the latter one being pharmacologically useful. As such, Levoleucovorin was approved by the FDA in 2008.
It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.
ly. This may produce severe adverse effects or even death.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
), generally administered as calcium or sodium folinate (or leucovorin calcium/sodium), is an adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
used in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
involving the drug methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
. It is also used in synergistic
Synergy
Synergy may be defined as two or more things functioning together to produce a result not independently obtainable.The term synergy comes from the Greek word from , , meaning "working together".-Definitions and usages:...
combination with the chemotherapy agent 5-fluorouracil.
Levofolinic acid and its salts are the enantiopure drug
Enantiopure drug
An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind differently to target receptors...
s. They are configurated S at the remaining asymmetric carbon atom (see below).
Folinic acid should be distinguished from folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
.
Mechanism of action
Folinic acid is a 5-formyl derivative of tetrahydrofolic acidTetrahydrofolic acid
Tetrahydrofolic acid, or tetrahydrofolate, is a folic acid derivative.-Metabolism:-Human synthesis:It is produced from dihydrofolic acid by dihydrofolate reductase...
. It is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate), and, thus, has vitamin activity that is equivalent to that of folic acid. However, since it does not require the action of dihydrofolate reductase
Dihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate.
Folinic acid, therefore, allows for some purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
/pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
synthesis to occur in the presence of dihydrofolate reductase inhibition, so that some normal DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
replication and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
transcription processes can proceed.
Therapeutic use
Folinic acid is administered at the appropriate time following methotrexateMethotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
as part of a total chemotherapeutic plan, where it may "rescue" bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and gastrointestinal mucosa cells from methotrexate. There is no apparent effect on preexisting methotrexate-induced nephrotoxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
.
While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be re-dosed until the methotrexate level is less than 5 x 10−8 M
Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase
Thymidylate synthase
Thymidylate synthetase is the enzyme used to generate thymidine monophosphate , which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair....
.
Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
dihydrofolate reductase inhibitors such as trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
and pyrimethamine
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
. Folinic acid may be prescribed in the treatment of toxoplasmosis
Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
retinitis, in combination with the folic acid antagonists pyrimethamine
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...
and sulfadiazine
Sulfadiazine
Sulfadiazine is a sulfonamide antibiotic.-Uses:It eliminates bacteria that cause infections by stopping the production of folic acid inside the bacterial cell, and is commonly used to treat urinary tract infections ....
.
Folinic acid has dextro- and levo-isomers, only the latter one being pharmacologically useful. As such, Levoleucovorin was approved by the FDA in 2008.
It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.
Citrovorum Factor
Citrovorum factor is a derivative of folacin metabolized in the liver that is required for the growth of Leuconostoc citrovorum. The synthesis of citrovorum factor from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems resulted in increased citrovorum factor activity in the cell-free supernatants.Note on administration
Folinic acid should not be administered intrathecalIntrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
ly. This may produce severe adverse effects or even death.