Folinic acid
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|---|---|
| Systematic (IUPAC) name | |
| (2S)-2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8- tetrahydro-1H-pteridin-6-yl)methylamino] benzoyl]amino}pentanedioic acid | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| Pregnancy cat. | A (AU) C (US) |
| Legal status | ℞ Prescription only |
| Routes | Intravenous, oral |
| Pharmacokinetic data | |
| Bioavailability | Dose dependent: |
| Protein binding | ~15% |
| Half-life | 6.2 hours |
| Excretion | Urinary |
| Identifiers | |
| CAS number | 1492-18-8  |
| ATC code | V03AF03 |
| PubChem | CID 6006 |
| DrugBank | DB00650 |
| ChemSpider | 5784 |
| UNII | RPR1R4C0P4 |
| ChEMBL | CHEMBL1679 |
| Chemical data | |
| Formula | C20H23N7O7 |
| Mol. mass | 473.44 g/mol |
| SMILES
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| Physical data | |
| Melt. point | 245 °C (473 °F) decomp |
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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.[1] 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.[2] 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.
History of discovery as Citrovorum factor
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.
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. 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.
Therapeutic use
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.[3]
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[4]
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.[5]
It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.[6]
Note on administration
Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.[7] And Folinic Acid should not be administered to pregnant woman because it can weaken the unborn baby's immune system
References
- ↑ 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
- ↑ Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.
- ↑ http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf
- ↑ 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.
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