|Systematic (IUPAC) name|
|Pregnancy cat.||A (AU) C (US)|
|Legal status||℞ Prescription only|
|Mol. mass||473.44 g/mol|
|Melt. point||245 °C (473 °F) decomp|
|(what is this?)|
Folinic acid (INN) 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 drugs (in this case, the levo form), and are the only molecules that are biologically active. They are configurated S at the remaining asymmetric carbon atom (see below).
Folinic acid was first discovered in 1948 as citrovorum factor and occasionally is still called by that name. 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. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
Folinic acid is administered at the appropriate time following methotrexate 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.
IMPORTANT NOTE: The active substance, when administered orally, it is immediately destroyed by the gastric juices. The Ca folinate salt is highly unstable at acid pH and thus the oral intake is completely useless and ineffective.
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., tetrahydrofolate), and, thus, has vitamin activity that is 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 was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This so-called "citrovorum factor," which then had an unknown structure, was 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 we know now, 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.
- Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (February 1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutat. Res. 397 (2): 221–8. doi:10.1016/S0027-5107(97)00216-9. PMID 9541646.
- http://www.jbc.org/content/200/1/223.full.pdf Citrovorum factor discovery
- "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.
- Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". Retrieved 2009-06-07.
- Ellis JM, Tan HK, Gilbert RE, et al (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, LF et al (1996). "Intrathecal Leucovorin After Intrathecal Methotrexate Overdose". J Pediatr Hematol Oncol 18 (3): 302–304. doi:10.1097/00043426-199608000-00014. PMID 8689347.
- Goldman ID, Matherly LH (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.