Folinic acid

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Not to be confused with folic acid.
Folinic acid
Folinic acid.svg
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
Trade names Many
AHFS/Drugs.com monograph
Pregnancy cat.
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 YesY
ATC code V03AF03
PubChem CID 6006
DrugBank DB00650
ChemSpider 5784 YesY
UNII RPR1R4C0P4 YesY
ChEMBL CHEMBL1679 YesY
Chemical data
Formula C20H23N7O7 
Mol. mass 473.44 g/mol
Physical data
Melt. point 245 °C (473 °F) decomp
 N (what is this?)  (verify)
Levofolinic acid

Folinic acid (INN) or leucovorin /lkˈvɔːrɪn/ (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.

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. 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.[3]

Levofolinic acid and its salts are the 2S- form of the molecule. They are the only molecules that are biologically active.

Medical use[edit]

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. No apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity.[4]

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.[5]

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.

Folinic acid has dextro- and levorotary isomers, only the latter one being pharmacologically useful. As such, levoleucovorin was approved by the FDA in 2008.[6]

It has been investigated for use in Down syndrome, but a benefit has not been demonstrated.[7]

Synonyms[edit]

5-formylterahydrofolate

Side effects[edit]

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.[8]

Mechanism of action[edit]

Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate), 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.[9]

Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal DNA replication processes can proceed.

History[edit]

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 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.

References[edit]

  1. ^ 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. 
  2. ^ http://www.jbc.org/content/200/1/223.full.pdf Citrovorum factor discovery
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.
  5. ^ http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf
  6. ^ Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". Retrieved 2009-06-07. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 

External links[edit]