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| Pronunciation | Leucovorin/ˌljuːkoʊˈvɔːrɪn/ |
| Trade names | Many |
| Other names | citrovorum factor, 5-formyltetrahydrofolate |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608038 |
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| Routes of administration | Intravenous, IM, by mouth |
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| Pharmacokinetic data | |
| Bioavailability | Dose dependent |
| Protein binding | ~15% |
| Eliminationhalf-life | 6.2 hours |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.328 |
| Chemical and physical data | |
| Formula | C20H23N7O7 |
| Molar mass | 473.446 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 245 °C (473 °F) decomp |
| Solubility in water | ~0.3[1] mg/mL (20 °C) |
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Folinic acid, also known asleucovorin, is a medication used to decrease the toxic effects ofmethotrexate andpyrimethamine.[2][3] It is also used in combination with5-fluorouracil to treatcolorectal cancer and pancreatic cancer, may be used to treatfolate deficiency that results inanemia, andmethanol poisoning.[3][4] It is taken by mouth,injection into a muscle, orinjection into a vein.[3]
Side effects may include trouble sleeping,allergic reactions, orfever.[2][3] Use inpregnancy orbreastfeeding is generally regarded as safe.[2] When used for anemia it is recommended thatpernicious anemia as a cause be ruled out first.[3] Folinic acid is a form offolic acid that does not require activation bydihydrofolate reductase to be useful to the body.[3]
Folinic acid was first made in 1945.[5] It is on theWorld Health Organization's List of Essential Medicines.[6]
Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).[7]
Folinic acid is given followingmethotrexate as part of a total chemotherapeutic plan, where it may protect againstbone marrow suppression or gastrointestinal mucosa inflammation. No apparent effect is seen on pre-existing methotrexate-inducednephrotoxicity.[8]
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 redosed until the methotrexate level is less than 5 x 10−8 M.[9]
Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate inrheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.[10]
Folinic acid is also used in combination with the chemotherapy agent5-fluorouracil in treatingcolon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibitingthymidylate synthase.
Folinic acid is also sometimes used to prevent toxic effects of high doses ofantimicrobialdihydrofolate reductase inhibitors such astrimethoprim andpyrimethamine, although its value for this indication has not been clearly established.[11] It may be prescribed in the treatment oftoxoplasmosisretinitis, in combination with the folic acid antagonistspyrimethamine andsulfadiazine.
Folinic acid is also used in the treatment ofcerebral folate deficiency, a syndrome in which the use offolic acid cannot normalize cerebrospinal fluid levels of5-MTHF.[12]
Inpyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine orpyridoxal phosphate fails to fully control the seizures.[13]
Folinic acid should not be administeredintrathecally. This may produce severe adverse effects or even death.[14] Severe neurotoxicity due to intrathecal folinic acid as treatment for intrathecally-administered methotrexate was first noted in an 11-year-old boy being treated for acute lymphocytic leukemia[14]
In cancer patients, rarehypersensitivity reactions to folinic acid have been described.[15]
Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severeenterocolitis, diarrhea, and dehydration.
Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment ofPneumocystis jirovecii (formerly known asPneumocystis carinii), a common cause of pneumonia in AIDS patients.[16]
Folinic acid is a 5-formyl derivative oftetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g.,5,10-methylenetetrahydrofolate,5-methyltetrahydrofolate), thus has vitamin activity equivalent to that of folic acid. Since it does not require the action ofdihydrofolate reductase for its conversion, its function as a vitamin is unaffected byinhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy. In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists.
Although the mechanism is not very clear, thepolyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells.[17]
Folinic acid, therefore, allows for somepurine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normalDNA replication processes can proceed.
Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability.[18] Levoleucovorin was approved by the FDA in 2008.[19]
Folinic acid was discovered as a needed growth factor for the bacteriumLeuconostoc citrovorum in 1948, by Sauberlich and Baumann.[20] This resulted in it being called "citrovorum factor," meaning citrovorum growth factor. It had an unknown structure, but was found to be a derivative of folate that had to be metabolized in the liver before it could support growth ofL. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished 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 (producing, as now known, the 5-formyl derivative), and from this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.[21]
Folinic acid should be distinguished fromfolic acid (vitamin B9). However, folinic acid is avitamer for folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S-form of the molecule. They are the only forms of the molecule that are known to be biologically active.
It is generally administered as thecalcium orsodium salt (calcium folinate (INN), sodium folinate, leucovorin calcium, leucovorin sodium).
