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{{Short description|Derivative of folic acid used in cancer treatment}}
{{Distinguish|folic acid}}
{{Distinguish|folic acid}}
{{Use dmy dates|date=March 2024}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
| Watchedfields = changed
| Watchedfields = changed
| verifiedrevid = 470454241
| verifiedrevid = 470454241
⚫
| IUPAC_name = (''2S'')-2-<nowiki/>{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-<br />tetrahydro-1''H''-pteridin-6-yl)methylamino]<br />benzoyl]amino}pentanedioic acid
| image = Folinic acid.svg
| image = Folinic acid.svg
| alt = Skeletal formula of folinic acid
| alt = Skeletal formula of folinic acid
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| image2 = Leucovorin molecule ball.png
| image2 = Leucovorin molecule ball.png
| alt2 = Ball-and-stick model of the folinic acid molecule
| alt2 = Ball-and-stick model of the folinic acid molecule

<!--Clinical data-->
<!--Clinical data-->
⚫
| synonyms = citrovorum factor, 5-formyltetrahydrofolate
| pronounce = Leucovorin {{IPAc-en|ˌ|lj|uː|k|oʊ|ˈ|v|ɔː|r|ɪ|n}}
| pronounce = Leucovorin {{IPAc-en|ˌ|lj|uː|k|oʊ|ˈ|v|ɔː|r|ɪ|n}}
| tradename = Many
| tradename = Many
| Drugs.com = {{drugs.com|monograph|leucovorin-calcium}}
| Drugs.com = {{drugs.com|monograph|leucovorin-calcium}}
| MedlinePlus = a608038
| DailyMedID = Leucovorin calcium
| pregnancy_AU = A
| pregnancy_AU = A
⚫
| routes_of_administration = [[intravenous therapy|Intravenous]], IM, by mouth
| pregnancy_US = C
| legal_status = OTC
| ATC_prefix = V03
⚫
| ATC_suffix = AF03
⚫
| routes_of_administration = [[intravenous therapy|intravenous]], IM, by mouth

⚫
<!--Pharmacokinetic data-->
<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

⚫
<!-- Pharmacokinetic data -->
| bioavailability = Dose dependent
| bioavailability = Dose dependent
| protein_bound = ~15%
| protein_bound = ~15%
| metabolism =
| metabolism =
| elimination_half-life = 6.2 hours
| elimination_half-life = 6.2 hours
| excretion = Urinary
| excretion = [[Kidney]]

<!--Identifiers-->
<!--Identifiers-->
| IUPHAR_ligand = 4816
| IUPHAR_ligand = 4816
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1492-18-8
| CAS_number = 1492-18-8
| ATC_prefix = V03
⚫
| ATC_suffix = AF03
| PubChem = 6006
| PubChem = 6006
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
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| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1679
| ChEMBL = 1679
⚫
| synonyms = citrovorum factor, 5-formyltetrahydrofolate

<!--Chemical data-->
<!--Chemical data-->
⚫
| IUPAC_name = (''2S'')-2-<nowiki/>{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-<br />tetrahydro-1''H''-pteridin-6-yl)methylamino]<br />benzoyl]amino}pentanedioic acid
| C=20 | H=23 | N=7 | O=7
| C=20 | H=23 | N=7 | O=7
| molecular_weight = 473.44 g/mol
| SMILES = O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O
| SMILES = O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| melting_high =
| melting_high =
| melting_notes = decomp
| melting_notes = decomp
| solubility = ~0.3<ref>{{Cite web|url=https://www.caymanchem.com/msdss/20383m.pdf|title=Safety Data Sheet Folinic Acid (calcium salt)|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=25 January 2018}}</ref>
| solubility = ~0.3<ref>{{Cite web|url=https://www.caymanchem.com/msdss/20383m.pdf|title=Safety Data Sheet Folinic Acid (calcium salt) |access-date=25 January 2018}}</ref>
}}
}}


<!-- Definition and medical uses -->
<!-- Definition and medical uses -->
'''Folinic acid''', also known as '''leucovorin''', is a medication used to decrease the toxic effects of [[methotrexate]] and [[pyrimethamine]].<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|pages=576–577|edition=69}}</ref><ref name=AHFS2016>{{cite web|title=Leucovorin Calcium|url=https://www.drugs.com/monograph/leucovorin-calcium.html|publisher=The American Society of Health-System Pharmacists|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20170510115807/https://www.drugs.com/monograph/leucovorin-calcium.html|archivedate=10 May 2017|df=}}</ref> 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]].<ref name=AHFS2016/><ref>{{cite book|last1=Munjal|first1=Y. P.|last2=Sharm|first2=Surendra K.|title=API Textbook of Medicine, Ninth Edition, Two Volume Set|date=2012|publisher=JP Medical Ltd|isbn=9789350250747|page=1945|url=https://books.google.ca/books?id=L7pW3yGjj7kC&pg=PA1945|language=en|deadurl=no|archiveurl=https://web.archive.org/web/20170510215410/https://books.google.ca/books?id=L7pW3yGjj7kC&pg=PA1945|archivedate=2017-05-10|df=}}</ref> It is taken by mouth, [[intramuscular|injection into a muscle]], or [[intravenous|injection into a vein]].<ref name=AHFS2016/>
'''Folinic acid''', also known as '''leucovorin''', is a medication used to decrease the toxic effects of [[methotrexate]] and [[pyrimethamine]].<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|pages=576–577|edition=69}}</ref><ref name=AHFS2016>{{cite web|title=Leucovorin Calcium|url=https://www.drugs.com/monograph/leucovorin-calcium.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170510115807/https://www.drugs.com/monograph/leucovorin-calcium.html|archive-date=10 May 2017}}</ref> It is also used in combination with [[5-fluorouracil]] to treat [[colorectal cancer]] and pancreatic cancer, may be used to treat [[folate deficiency]] that results in [[anemia]], and [[methanol poisoning]].<ref name=AHFS2016/><ref>{{cite book| vauthors = Munjal YP, Sharm SK |title=API Textbook of Medicine, Ninth Edition, Two Volume Set|date=2012|publisher=JP Medical Ltd|isbn=9789350250747|page=1945|url=https://books.google.com/books?id=L7pW3yGjj7kC&pg=PA1945|language=en|url-status=live|archive-url=https://web.archive.org/web/20170510215410/https://books.google.ca/books?id=L7pW3yGjj7kC&pg=PA1945|archive-date=10 May 2017}}</ref> It is taken by mouth, [[intramuscular|injection into a muscle]], or [[intravenous|injection into a vein]].<ref name=AHFS2016/>


<!-- Side effects and mechanism -->
<!-- Side effects and mechanism -->
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<!-- History and culture -->
<!-- History and culture -->
Folinic acid was first made in 1945.<ref>{{cite book|last1=Sneader|first1=Walter|title=Drug Discovery: A History|date=2005|publisher=John Wiley & Sons|isbn=9780471899792|page=235|url=https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA235|language=en|deadurl=no|archiveurl=https://web.archive.org/web/20170510233831/https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA235|archivedate=2017-05-10|df=}}</ref> It is on the [[World Health Organization's List of Essential Medicines]], the most effective and safe medicines needed in a [[health system]].<ref name=WHO19th>{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}}</ref> In the United Kingdom it costs the [[NHS]] about 4.62 pounds per 30&nbsp;mg vial.<ref name=BNF69/>
Folinic acid was first made in 1945.<ref>{{cite book| vauthors = Sneader W |title=Drug Discovery: A History|date=2005|publisher=John Wiley & Sons|isbn=9780471899792|page=235|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA235|language=en|url-status=live|archive-url=https://web.archive.org/web/20170510233831/https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA235|archive-date=10 May 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>


== Medical use ==
== Medical use ==
[[File:Levofolinic acid.svg|thumb|Levofolinic acid]]
[[File:Levofolinic acid.svg|thumb|Levofolinic acid]]
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]].<ref>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|date=February 2015}}</ref> Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).<ref>{{cite journal |pmid=3257913|year=1988|author1=McGuire|first1=B. W.|title=Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration|journal=Clinical Pharmacy|volume=7|issue=1|pages=52–8|last2=Sia|first2=L. L.|last3=Leese|first3=P. T.|last4=Gutierrez|first4=M. L.|last5=Stokstad|first5=E. L.}}</ref>
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]].<ref>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|date=February 2015}}</ref> Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).<ref>{{cite journal | vauthors = McGuire BW, Sia LL, Leese PT, Gutierrez ML, Stokstad EL | title = Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration | journal = Clinical Pharmacy | volume = 7 | issue = 1 | pages = 52–58 | date = January 1988 | pmid = 3257913 }}</ref>


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<sup>−8</sup> M.<ref>{{cite web |url=http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf |title=Archived copy |accessdate=2014-01-07 |deadurl=no |archiveurl=https://web.archive.org/web/20081010050826/http://www.cancercare.on.ca/pdfdrugs/Leucovo.pdf |archivedate=2008-10-10 |df= }}{{full citation needed|date=February 2015}}</ref>
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<sup>−8</sup> M.<ref>{{cite web | title = Leucovorin | work = CCO Formulary |url=http://www.cancercare.on.ca/pdfdrugs/leucovo.pdf |access-date=7 January 2014 |url-status=dead |archive-url=https://web.archive.org/web/20081010050826/http://www.cancercare.on.ca/pdfdrugs/Leucovo.pdf |archive-date=10 October 2008 }}</ref>


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.<ref>{{cite journal |doi=10.1002/14651858.CD000951.pub2|pmid=23728635|title=Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis|journal=Cochrane Database of Systematic Reviews|volume=5|issue=5|pages=CD000951|year=2013|last1=Shea|first1=Beverley|last2=Swinden|first2=Michael V|last3=Tanjong Ghogomu|first3=Elizabeth|last4=Ortiz|first4=Zulma|last5=Katchamart|first5=Wanruchada|last6=Rader|first6=Tamara|last7=Bombardier|first7=Claire|last8=Wells|first8=George A|last9=Tugwell|first9=Peter}}</ref>
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.<ref>{{cite journal | vauthors = Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P | display-authors = 6 | title = Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD000951 | date = May 2013 | pmid = 23728635 | pmc = 7046011 | doi = 10.1002/14651858.CD000951.pub2 }}</ref>


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 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 is also sometimes used to prevent toxic effects of high doses of [[antimicrobial]] dihydrofolate reductase inhibitors such as [[trimethoprim]] and [[pyrimethamine]], although its value for this indication has not been clearly established.<ref>{{cite book | vauthors = Trubiano JA, Grayson ML |doi=10.1201/9781498747967 |title=Kucers' the Use of Antibiotics |edition=7th |url=https://www.taylorfrancis.com/books/edit/10.1201/9781498747967/kucers-use-antibiotics-lindsay-grayson-sara-cosgrove-suzanne-crowe-lindsay-grayson-william-hope-james-mccarthy-john-mills-johan-mouton-david-paterson |year=2017 |isbn=9781498747967 | veditors = Grayson ML, Cosgrove S, Crowe S, Hope W, McCarthy J, Mills J, Mouton JW, Paterson D |chapter=Trimethoprim and Trimethoprim–Sulfamethoxazole (Cotrimoxazole) |chapter-url=https://www.taylorfrancis.com/chapters/edit/10.1201/9781498747967-92/trimethoprim-trimethoprim%E2%80%93sulfamethoxazole-cotrimoxazole-jason-trubiano-lindsay-grayson |page=1652 |publisher=CRC Press }}</ref> It may be prescribed in the treatment of [[toxoplasmosis]] [[retinitis]], in combination with the folic acid antagonists [[pyrimethamine]] and [[sulfadiazine]].


Folinic acid is also used in the treatment of [[cerebral folate deficiency]], a syndrome in which the use of [[folic acid]] cannot normalize cerebrospinal fluid levels of [[5-MTHF]].<ref name=Gordon2009>{{cite journal |last1=Gordon |first1=N |title=Cerebral folate deficiency. |journal=Developmental Medicine and Child Neurology |date=2009 |volume=51 |issue=3 |pages=180–182 |doi=10.1111/j.1469-8749.2008.03185.x |pmid=19260931}}</ref>
Folinic acid is also used in the treatment of [[cerebral folate deficiency]], a syndrome in which the use of [[folic acid]] cannot normalize cerebrospinal fluid levels of [[5-MTHF]].<ref name=Gordon2009>{{cite journal | vauthors = Gordon N | title = Cerebral folate deficiency | journal = Developmental Medicine and Child Neurology | volume = 51 | issue = 3 | pages = 180–182 | date = March 2009 | pmid = 19260931 | doi = 10.1111/j.1469-8749.2008.03185.x | s2cid = 7373721 }}</ref>

In [[pyridoxine-dependent epilepsy]], folinic acid may be used as additional therapy if pyridoxine or [[pyridoxal phosphate]] fails to fully control the seizures.<ref name="pmid35053812">{{cite journal | vauthors = Kaminiów K, Pająk M, Pająk R, Paprocka J | title = Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures | journal = Brain Sciences | volume = 12 | issue = 1 | page = 65 | date = December 2021 | pmid = 35053812 | pmc = 8773593 | doi = 10.3390/brainsci12010065 | doi-access = free }}</ref>


== Side effects ==
== Side effects ==
Folinic acid should not be administered [[intrathecal]]ly. This may produce severe adverse effects or even death.<ref>{{cite journal |doi=10.1097/00043426-199608000-00014|pmid=8689347|title=Intrathecal Leucovorin After Intrathecal Methotrexate Overdose|journal=Journal of Pediatric Hematology/Oncology|volume=18|issue=3|pages=302–4|year=1996|last1=Jardine|first1=Lawrence F.|last2=Ingram|first2=Lewis C.|last3=Bleyer|first3=W. Archie}}</ref>
Folinic acid should not be administered [[intrathecal]]ly. This may produce severe adverse effects or even death.<ref>{{cite journal | vauthors = Jardine LF, Ingram LC, Bleyer WA | title = Intrathecal leucovorin after intrathecal methotrexate overdose | journal = Journal of Pediatric Hematology/Oncology | volume = 18 | issue = 3 | pages = 302–304 | date = August 1996 | pmid = 8689347 | doi = 10.1097/00043426-199608000-00014 | s2cid = 43280375 }}</ref>

In cancer patients, rare [[hypersensitivity]] reactions to folinic acid have been described.<ref name="pmid26042586">{{cite journal | vauthors = Florit-Sureda M, Conde-Estévez D, Vidal J, Montagut C | title = Hypersensitivity reaction caused by folinic acid administration: a case report and literature review | journal = Journal of Chemotherapy | volume = 28 | issue = 6 | pages = 500–505 | date = December 2016 | pmid = 26042586 | doi = 10.1179/1973947815Y.0000000048 | hdl-access = free | s2cid = 25420102 | hdl = 10230/27696 }}</ref>


== Drug interactions ==
== Drug interactions ==
[[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.<ref>{{cite journal |pmid=7627739|year=1995|author1=Trissel|first1=L. A.|title=Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium|journal=American Journal of Health-System Pharmacy |volume=52|issue=7|pages=710–5|last2=Martinez|first2=J. F.|last3=Xu|first3=Q. A.}}</ref>
[[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.<ref>{{cite journal |pmid=11876516|year=2002|author1=Razavi|first1=B|title=Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use|journal=Infection|volume=30|issue=1|pages=41–2|last2=Lund|first2=B|last3=Allen|first3=B. L.|last4=Schlesinger|first4=L|doi=10.1007/s15010-001-1172-0}}</ref>
[[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.<ref>{{cite journal | vauthors = Razavi B, Lund B, Allen BL, Schlesinger L | title = Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use | journal = Infection | volume = 30 | issue = 1 | pages = 41–42 | date = January 2002 | pmid = 11876516 | doi = 10.1007/s15010-001-1172-0 | s2cid = 35513636 }}</ref>


== Mechanism of action ==
== 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 [[enzyme inhibition|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.<ref name="pmid2448654">{{cite journal |pmid=2448654|year=1987|author1=Goldman|first1=I. D.|title=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|journal=NCI Monographs |issue=5|pages=17–26|last2=Matherly|first2=L. H.}}</ref>
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 [[enzyme inhibition|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.<ref name="pmid2448654">{{cite journal | vauthors = Goldman ID, Matherly LH | title = 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 | journal = NCI Monographs | issue = 5 | pages = 17–26 | year = 1987 | pmid = 2448654 }}</ref>


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.
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.


Folinic acid has dextro- and levorotary isomers, only the latter one being pharmacologically useful. As such, levoleucovorin was approved by the FDA in 2008.<ref>{{cite web |url=https://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html |author=Drugs.com |title=FDA Approves Levoleucovorin |date=2008-05-07 |accessdate=2009-06-07 |deadurl=no |archiveurl=https://web.archive.org/web/20090702033819/http://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html |archivedate=2009-07-02 |df= }}</ref>
Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability.<ref>{{cite journal | vauthors = Kovoor PA, Karim SM, Marshall JL | title = Is levoleucovorin an alternative to racemic leucovorin? A literature review | journal = Clinical Colorectal Cancer | volume = 8 | issue = 4 | pages = 200–206 | date = October 2009 | pmid = 19822510 | doi = 10.3816/CCC.2009.n.034 }}</ref> Levoleucovorin was approved by the FDA in 2008.<ref>{{cite web |url=https://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html | work = Drugs.com |title=FDA Approves Levoleucovorin |date=7 May 2008 |access-date=7 June 2009 |url-status=live |archive-url=https://web.archive.org/web/20090702033819/http://www.drugs.com/newdrugs/fda-approves-new-application-levoleucovorin-spectrum-s-first-proprietary-oncology-drug-888.html |archive-date=2 July 2009 }}</ref>


== History ==
== History ==
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.{{citation needed|date=February 2015}}
Folinic acid was discovered as a needed growth factor for the bacterium ''[[Leuconostoc citrovorum]]'' in 1948, by Sauberlich and Baumann.<ref>{{Cite journal |date=2009-04-27 |title=A New Form of Folic Acid-The Levconostoc Citrovorum Factor |url=https://academic.oup.com/nutritionreviews/article-lookup/doi/10.1111/j.1753-4887.1950.tb02478.x |journal=Nutrition Reviews |language=en |volume=8 |issue=9 |pages=282–284 |doi=10.1111/j.1753-4887.1950.tb02478.x}}</ref> 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.<ref>Rabinowitz, J. C., & Pricer Jr, W. E. (1956). Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid. ''Journal of the American Chemical Society'', ''78''(21), 5702-5704.</ref>


==Names==
==Names==
Folinic acid should be distinguished from [[folic acid]] (vitamin B<sub>9</sub>). 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.
Folinic acid should be distinguished from [[folic acid]] (vitamin B<sub>9</sub>). 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.


It is generally administered as the [[calcium]] or [[sodium]] salt (calcium folinate ([[International Nonproprietary Name|INN]]), sodium folinate, leucovorin calcium, leucovorin sodium).
It is generally administered as the [[calcium]] or [[sodium]] salt (calcium folinate ([[International Nonproprietary Name|INN]]), sodium folinate, leucovorin calcium, leucovorin sodium).
Line 105: Line 135:


== External links ==
== External links ==
* {{cite web | title=Leucovorin | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a682336.html }}
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Folinic+acid U.S. National Library of Medicine: Drug Information Portal – Folinic acid]


{{Detoxifying agents for antineoplastic treatment}}
{{Detoxifying agents for antineoplastic treatment}}
{{Vitamin}}
{{Vitamin}}
{{Portal bar|Medicine}}


[[Category:Chemotherapeutic adjuvants]]
[[Category:Chemotherapeutic adjuvants]]
[[Category:Folates]]
[[Category:Folates]]
[[Category:World Health Organization essential medicines]]
[[Category:World Health Organization essential medicines]]
[[Category:RTT]]
[[Category:Wikipedia medicine articles ready to translate]]

{{portal bar|Pharmacy and pharmacology|Medicine}}

Latest revision as of 22:22, 23 July 2024

Not to be confused with folic acid.

Folinic acid
Skeletal formula of folinic acid
Ball-and-stick model of the folinic acid molecule
Clinical data
PronunciationLeucovorin /ˌljuːkoʊˈvɔːrɪn/
Trade namesMany
Other namescitrovorum factor, 5-formyltetrahydrofolate
AHFS/Drugs.comMonograph
MedlinePlusa608038
License data
Pregnancy
category
  • AU: A
Routes of
administration		Intravenous, IM, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityDose dependent
Protein binding~15%
Elimination half-life6.2 hours
ExcretionKidney
Identifiers
  • (2S)-2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-
    tetrahydro-1H-pteridin-6-yl)methylamino]
    benzoyl]amino}pentanedioic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.328 Edit this at Wikidata
Chemical and physical data
FormulaC20H23N7O7
Molar mass473.446 g·mol−1
3D model (JSmol)
Melting point245 °C (473 °F) decomp
Solubility in water~0.3[1] mg/mL (20 °C)
  • O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O
  • InChI=1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1 checkY
  • Key:VVIAGPKUTFNRDU-ABLWVSNPSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine.[2][3] It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning.[3][4] It is taken by mouth, injection into a muscle, or injection into a vein.[3]

Side effects may include trouble sleeping, allergic reactions, or fever.[2][3] Use in pregnancy or breastfeeding is generally regarded as safe.[2] When used for anemia it is recommended that pernicious anemia as a cause be ruled out first.[3] Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.[3]

Folinic acid was first made in 1945.[5] It is on the World Health Organization's List of Essential Medicines.[6]

Medical use

[edit]
Levofolinic acid

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.[7] Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).[8]

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.[9]

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.[10]

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, although its value for this indication has not been clearly established.[11] It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.

Folinic acid is also used in the treatment of cerebral folate deficiency, a syndrome in which the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF.[12]

In pyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine or pyridoxal phosphate fails to fully control the seizures.[13]

Side effects

[edit]

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.[14]

In cancer patients, rare hypersensitivity reactions to folinic acid have been described.[15]

Drug interactions

[edit]

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.[16]

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., 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.[17]

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.

Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability.[18] Levoleucovorin was approved by the FDA in 2008.[19]

History

[edit]

Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann.[20] 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.[21]

Names

[edit]

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.

It is generally administered as the calcium or sodium salt (calcium folinate (INN), sodium folinate, leucovorin calcium, leucovorin sodium).

References

[edit]
  1. ^ "Safety Data Sheet Folinic Acid (calcium salt)" (PDF). Retrieved 25 January 2018.
  2. ^ a b c British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 576–577. ISBN 9780857111562.
  3. ^ a b c d e f "Leucovorin Calcium". The American Society of Health-System Pharmacists. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
  4. ^ Munjal YP, Sharm SK (2012). API Textbook of Medicine, Ninth Edition, Two Volume Set. JP Medical Ltd. p. 1945. ISBN 9789350250747. Archived from the original on 10 May 2017.
  5. ^ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 235. ISBN 9780471899792. Archived from the original on 10 May 2017.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ 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]
  8. ^ McGuire BW, Sia LL, Leese PT, Gutierrez ML, Stokstad EL (January 1988). "Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration". Clinical Pharmacy. 7 (1): 52–58. PMID 3257913.
  9. ^ "Leucovorin" (PDF). CCO Formulary. Archived from the original (PDF) on 10 October 2008. Retrieved 7 January 2014.
  10. ^ Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. (May 2013). "Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis". The Cochrane Database of Systematic Reviews. 5 (5): CD000951. doi:10.1002/14651858.CD000951.pub2. PMC 7046011. PMID 23728635.
  11. ^ Trubiano JA, Grayson ML (2017). "Trimethoprim and Trimethoprim–Sulfamethoxazole (Cotrimoxazole)". In Grayson ML, Cosgrove S, Crowe S, Hope W, McCarthy J, Mills J, Mouton JW, Paterson D (eds.). Kucers' the Use of Antibiotics (7th ed.). CRC Press. p. 1652. doi:10.1201/9781498747967. ISBN 9781498747967.
  12. ^ Gordon N (March 2009). "Cerebral folate deficiency". Developmental Medicine and Child Neurology. 51 (3): 180–182. doi:10.1111/j.1469-8749.2008.03185.x. PMID 19260931. S2CID 7373721.
  13. ^ Kaminiów K, Pająk M, Pająk R, Paprocka J (December 2021). "Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures". Brain Sciences. 12 (1): 65. doi:10.3390/brainsci12010065. PMC 8773593. PMID 35053812.
  14. ^ Jardine LF, Ingram LC, Bleyer WA (August 1996). "Intrathecal leucovorin after intrathecal methotrexate overdose". Journal of Pediatric Hematology/Oncology. 18 (3): 302–304. doi:10.1097/00043426-199608000-00014. PMID 8689347. S2CID 43280375.
  15. ^ Florit-Sureda M, Conde-Estévez D, Vidal J, Montagut C (December 2016). "Hypersensitivity reaction caused by folinic acid administration: a case report and literature review". Journal of Chemotherapy. 28 (6): 500–505. doi:10.1179/1973947815Y.0000000048. hdl:10230/27696. PMID 26042586. S2CID 25420102.
  16. ^ Razavi B, Lund B, Allen BL, Schlesinger L (January 2002). "Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use". Infection. 30 (1): 41–42. doi:10.1007/s15010-001-1172-0. PMID 11876516. S2CID 35513636.
  17. ^ 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.
  18. ^ Kovoor PA, Karim SM, Marshall JL (October 2009). "Is levoleucovorin an alternative to racemic leucovorin? A literature review". Clinical Colorectal Cancer. 8 (4): 200–206. doi:10.3816/CCC.2009.n.034. PMID 19822510.
  19. ^ "FDA Approves Levoleucovorin". Drugs.com. 7 May 2008. Archived from the original on 2 July 2009. Retrieved 7 June 2009.
  20. ^ "A New Form of Folic Acid-The Levconostoc Citrovorum Factor". Nutrition Reviews. 8 (9): 282–284. 27 April 2009. doi:10.1111/j.1753-4887.1950.tb02478.x.
  21. ^ Rabinowitz, J. C., & Pricer Jr, W. E. (1956). Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid. Journal of the American Chemical Society, 78(21), 5702-5704.
[edit]
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