Folinic acid

Folinic acid
Folinic acid
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  ?
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 APRD00698
ChemSpider 5784 YesY
UNII RPR1R4C0P4 YesY
ChEMBL CHEMBL1679 YesY
Chemical data
Formula C20H23N7O7 
Mol. mass 473.44 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  acid (verify)
Levofolinic acid

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. They are configurated S at the remaining asymmetric carbon atom (see below).

Folinic acid should be distinguished from folic acid.

Contents

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.[2]

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[3]

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.[4]

It has been investigated for use in Down's syndrome, but a benefit has not been demonstrated.[5]

Citrovorum Factor

Citrovorum factor is a derivative of folacin metabolized in the liver that is required for the growth of Leuconostoc citrovorum. The synthesis of citrovorum factor 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.

Note on administration

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.[6]

References

  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. http://linkinghub.elsevier.com/retrieve/pii/S0027-5107(97)00216-9. 
  2. ^ Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.
  3. ^ www.cancercare.on.ca/pdfdrugs/leucovo.pdf
  4. ^ Drugs.com (2008-05-07). "FDA Approves Levoleucovorin". http://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html. Retrieved 2009-06-07. 
  5. ^ 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. http://bmj.com/cgi/pmidlookup?view=long&pmid=18296460. 
  6. ^ 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. http://www.jpho-online.com/pt/re/jpho/abstract.00043426-199608000-00014.htm. 

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Look at other dictionaries:

  • folinic acid — [fō lin′ik] n. [ FOL(IC ACID) + IN1 + IC] the active substance, C20H23N7O7, into which folic acid is converted in body tissue …   English World dictionary

  • folinic acid — 1. The active form of folic acid that acts as a formyl group carrier in transformylation reactions; the calcium salt, leucovorin calcium, has therapeutic use. 2. The term is occasionally applied to other folates. SYN: citrovorum factor …   Medical dictionary

  • folinic acid — a derivative of folic acid involved in purine synthesis. Administered by mouth or by injection in the form of its calcium or disodium salts, it is used to reverse the biological effects of methotrexate and other dihydrofolate reductase inhibitors …   The new mediacal dictionary

  • folinic acid — (Biochemistry) citrovorum factor, derivative of folic acid (used to treat anemia resulting from a folic acid deficiency), active metabolite of folic acid …   English contemporary dictionary

  • folinic acid — fōˈlinik noun Etymology: folic + in + ic : any of several natural or synthetic acids (as leucovorin) that are metabolically active forms of folic acid and support the growth of certain bacteria (as Leuconostoc citrovorum) called also citrovorum… …   Useful english dictionary

  • folinic acid — /foh lin ik/, Biochem., Pharm. a crystalline, slightly water soluble solid, C20H23N7O7, produced by fermentation or derived from folic acid, used in medicine in the treatment of certain anemias. [1945 50; FOL(IC) + IN2 + IC] * * * …   Universalium

  • folinic acid — noun A particular drug used in the treatment of cancer. Syn: leucovorin …   Wiktionary

  • folinic acid-SF — noun see leucovorin …   Useful english dictionary

  • Кислота Фолиновая (Folinic Acid) — производная фолиевой кислоты, участвующая в синтезе пурина. Назначается внутрь или в инъекциях; применяется для получения эффектов, обратных биологическому действию метотрексата и других ингибиторов дигидрофолата редуктазы, а также для… …   Медицинские термины

  • Folic acid — Folic acid …   Wikipedia

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