|Synonyms||citrovorum factor, 5-formyltetrahydrofolate|
|intravenous, IM, by mouth|
|Elimination half-life||6.2 hours|
|Chemical and physical data|
|Molar mass||473.44 g/mol|
|3D model (JSmol)|
|Melting point||245 °C (473 °F) decomp|
|Solubility in water||~0.3 mg/mL (20 °C)|
|(what is this?)|
Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.
Side effects may include trouble sleeping, allergic reactions, or fever. Use in pregnancy or breastfeeding is generally regarded as safe. When used for anemia it is recommended that pernicious anemia as a cause be ruled out first. Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.
Folinic acid was first made in 1945. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. In the United Kingdom it costs the NHS about 4.62 pounds per 30 mg vial.
Folinic acid is given following methotrexate as part of a total chemotherapeutic plan, where it may protect against bone marrow suppression or gastrointestinal mucosa inflammation. No apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity. Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).
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.
Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in rheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.
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. It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.
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 severe enterocolitis, 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 of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients.
Mechanism of action
Folinic acid is a 5-formyl derivative of tetrahydrofolic 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 of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition 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, the polyglutamylation 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.
Folinic acid has dextro- and levorotary isomers, only the latter one being pharmacologically useful. As such, levoleucovorin was approved by the FDA in 2008.
Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. 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 of L. 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.
Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer 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.
- "Safety Data Sheet Folinic Acid (calcium salt)" (PDF). Retrieved 25 January 2018.
- British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 576–577. ISBN 9780857111562.
- "Leucovorin Calcium". The American Society of Health-System Pharmacists. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
- Munjal, Y. P.; Sharm, Surendra K. (2012). API Textbook of Medicine, Ninth Edition, Two Volume Set. JP Medical Ltd. p. 1945. ISBN 9789350250747. Archived from the original on 2017-05-10.
- Sneader, Walter (2005). Drug Discovery: A History. John Wiley & Sons. p. 235. ISBN 9780471899792. Archived from the original on 2017-05-10.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.[page needed]
- McGuire, B. W.; Sia, L. L.; Leese, P. T.; Gutierrez, M. L.; Stokstad, E. L. (1988). "Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration". Clinical pharmacy. 7 (1): 52–8. PMID 3257913.
- "Archived copy" (PDF). Archived (PDF) from the original on 2008-10-10. Retrieved 2014-01-07. [full citation needed]
- Shea, Beverley; Swinden, Michael V; Tanjong Ghogomu, Elizabeth; Ortiz, Zulma; Katchamart, Wanruchada; Rader, Tamara; Bombardier, Claire; Wells, George A; Tugwell, Peter (2013). "Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis". Cochrane Database of Systematic Reviews. 5: CD000951. doi:10.1002/14651858.CD000951.pub2. PMID 23728635.
- Ellis, J. M.; Tan, H. K.; Gilbert, R. E.; Muller, D. P.; Henley, W; Moy, R; Pumphrey, R; Ani, C; Davies, S; Edwards, V; Green, H; Salt, A; Logan, S (March 2008). "Supplementation with antioxidants and folinic acid for children with Down's syndrome: Randomised controlled trial". BMJ. 336 (7644): 594–7. doi:10.1136/bmj.39465.544028.AE. PMC 2267988. PMID 18296460.
- Jardine, Lawrence F.; Ingram, Lewis C.; Bleyer, W. Archie (1996). "Intrathecal Leucovorin After Intrathecal Methotrexate Overdose". Journal of Pediatric Hematology/Oncology. 18 (3): 302–4. doi:10.1097/00043426-199608000-00014. PMID 8689347.
- Trissel, L. A.; Martinez, J. F.; Xu, Q. A. (1995). "Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium". American Journal of Health-System Pharmacy. 52 (7): 710–5. PMID 7627739.
- Razavi, B; Lund, B; Allen, B. L.; Schlesinger, L (2002). "Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use". Infection. 30 (1): 41–2. doi:10.1007/s15010-001-1172-0. PMID 11876516.
- Goldman, I. D.; Matherly, L. H. (1987). "Biochemical factors in the selectivity of leucovorin rescue: Selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates". NCI monographs (5): 17–26. PMID 2448654.
- Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". Archived from the original on 2009-07-02. Retrieved 2009-06-07.