Levomefolic acid

{{Chembox | ImageFile=5-Methyltetrahydrofolate.png | ImageClass = skin-invert-image | ImageSize=220px | IUPACName=(2''S'')-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid | OtherNames=(L-5-Me-THFA, L-5-Me-H4FA), anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H4F), L-methylfolate Metafolin |Section1={{Chembox Identifiers | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 8S95DH25XC | UNII1_Ref = {{fdacite|correct|FDA}} | UNII1 = A9R10K3F2F | UNII1_Comment = (calcium salt) | ChemSpiderID = 392351 | ChEBI = 136009 | SMILES = CN1c2c([nH]c(nc2=O)N)NC[C@@H]1CNc3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O | InChI = 1/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12-,13-/m0/s1 | InChIKey = ZNOVTXRBGFNYRX-STQMWFEEBP | StdInChI = 1S/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12-,13-/m0/s1 | StdInChIKey = ZNOVTXRBGFNYRX-STQMWFEESA-N | CASNo= 31690-09-2 | CASNo1 = 151533-22-1 | CASNo1_Comment = (calcium salt) | PubChem=444412 | PubChem1 = 15341110 | PubChem1_Comment = (calcium salt) | KEGG = D09353 | MeSHName=5-methyltetrahydrofolate

}} |Section2={{Chembox Properties | C=20 | H=25 | N=7 | O=6 | Appearance= | Density= | MeltingPt= | BoilingPt= | Solubility= }} |Section7={{Chembox Hazards | MainHazards= | FlashPt= | AutoignitionPt = }} |Section6={{Chembox Pharmacology | ATCCode_prefix = B03 | ATCCode_suffix = BB51 | AdminRoutes = oral, transdermal, subcutaneous | Bioavail = | Metabolism = | HalfLife = | ProteinBound = | Excretion = | Legal_status = | Legal_US = OTC | Legal_US_comment = | Legal_UK = | Legal_AU = | Legal_CA = | Pregnancy_category= | Pregnancy_AU = }} }}

'''Levomefolic acid''' (INN, also known as '''L-5-MTHF''', '''L-methylfolate''' and '''L-5-methyltetrahydrofolate''' and '''(6''S'')-5-methyltetrahydrofolate''', and '''(6''S'')-5-MTHF''') is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood–brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active.<ref name="Pietrzik">{{cite journal | vauthors = Pietrzik K, Bailey L, Shane B | title = Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics | journal = Clinical Pharmacokinetics | volume = 49 | issue = 8 | pages = 535–48 | date = August 2010 | pmid = 20608755 | doi = 10.2165/11532990-000000000-00000 | s2cid = 12876272 }}</ref> Systematic reviews suggest that adjunctive L-methylfolate modestly improves symptoms in major depressive disorder.<ref name=":0" /><ref name=":1" />

It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate. Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (MTHF) and used to recycle homocysteine back to methionine by methionine synthase (MS).<ref name="pubchem444412">{{citation|url=https://pubchem.ncbi.nlm.nih.gov/compound/444412|title=5-methyltetrahydrofolate – Compound Summary |work=PubChem|publisher=NCBI|access-date=2012-09-25}}</ref>

L-methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or parenteral administration. Peak concentrations were found to be more than seven times higher than folic acid (129 ng/ml vs. 14.1 ng/ml).<ref>{{cite web | url = http://intetlab.com/site/products/Cerefolin-NAC_package-insert_%204-26-10.pdf | title = CerefolinNAC Caplets Package Insert }}</ref>

Patients at risk for vitamin B12 deficiency should consult with their medical provider prior to taking L-Methylfolate. The interrelationship between these two vitamins (L-Methylfolate and B12) is best explained by the methyl trap hypothesis.<ref>{{cite journal | title = Vitamin B12-folate interrelationships | date = 1985 | pmid = 3927946 | last1 = Shane | first1 = B. | last2 = Stokstad | first2 = E. L. | journal = Annual Review of Nutrition | volume = 5 | pages = 115–141 | doi = 10.1146/annurev.nu.05.070185.000555 }}</ref><ref>{{cite journal | title = Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap | date = 2006 | pmid = 16445837 | last1 = Smulders | first1 = Y. M. | last2 = Smith | first2 = D. E. | last3 = Kok | first3 = R. M. | last4 = Teerlink | first4 = T. | last5 = Swinkels | first5 = D. W. | last6 = Stehouwer | first6 = C. D. | last7 = Jakobs | first7 = C. | journal = British Journal of Haematology | volume = 132 | issue = 5 | pages = 623–629 | doi = 10.1111/j.1365-2141.2005.05913.x }}</ref>

==Metabolism==

[[File:MTHFR metabolism.svg|class=skin-invert-image|center|thumb|650px|MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia. 5-MTHF: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; BAX: Bcl-2-associated X protein; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CGL: cystathionine gamma-lyase; DHF: dihydrofolate (vitamin B9); DMG: dimethylglycine; dTMP: thymidine monophosphate; dUMP: deoxyuridine monophosphate; FAD+ flavine adenine dicucleotide; FTHF: 10-formyltetrahydrofolate; MS: methionine synthase; MTHFR: methylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAME: S-adenosyl-L-methionine; THF: tetrahydrofolate.]]

==Medical uses==

=== Major depressive disorder and other psychiatric conditions === Systematic reviews suggest that adjunctive L-methylfolate modestly improves symptoms in major depressive disorder and may benefit other psychiatric conditions with good tolerability.<ref name=":0">{{Cite journal |last1=Maruf |first1=Abdullah Al |last2=Poweleit |first2=Ethan A. |last3=Brown |first3=Lisa C. |last4=Strawn |first4=Jeffrey R. |last5=Bousman |first5=Chad A. |date=2022 |title=Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders |journal=Pharmacopsychiatry |volume=55 |issue=3 |pages=139–147 |doi=10.1055/a-1681-2047 |issn=1439-0795 |pmid=34794190}}</ref><ref name=":1">{{Cite journal |last1=Lam |first1=Nelson Siu Kei |last2=Long |first2=Xin Xin |last3=Li |first3=Xuegang |last4=Saad |first4=Mirette |last5=Lim |first5=Florence |last6=Doery |first6=James CG |last7=Griffin |first7=Robert C. |last8=Galletly |first8=Cherrie |date=2022 |title=The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review |journal=Biomedicine & Pharmacotherapy |language=en |volume=146 |article-number=112541 |doi=10.1016/j.biopha.2021.112541 |pmid=34953391 |s2cid=245436052 |doi-access=free}}</ref> In patients with depression augmenting SSRI/SNRI treatment, L-methylfolate augmentation led to higher medication adherence and lower health care utilization and costs compared to augmentation with second-generation atypical antipsychotics.<ref>{{cite journal | vauthors = Wade RL, Kindermann SL, Hou Q, Thase ME | title = Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy | journal = Journal of Managed Care Pharmacy | volume = 20 | issue = 1 | pages = 76–85 | date = January 2014 | pmid = 24372461 | doi = 10.18553/jmcp.2014.20.1.76 | doi-access = free | pmc = 10438233 }}</ref>

=== Cardiovascular disease and cancer ===

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease<ref>{{cite journal | vauthors = Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW | title = Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease | journal = British Journal of Pharmacology | volume = 141 | issue = 5 | pages = 825–30 | date = March 2004 | pmid = 14769778 | pmc = 1574248 | doi = 10.1038/sj.bjp.0705446 | publisher = Nature Publishing Group }}</ref> and advanced cancers such as breast and colorectal cancers.<ref name="StröhleWolters2005">{{cite journal | vauthors = Ströhle A, Wolters M, Hahn A | title = Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review) | journal = International Journal of Oncology | volume = 26 | issue = 6 | pages = 1449–64 | date = June 2005 | pmid = 15870856 | doi = 10.3892/ijo.26.6.1449 }}</ref> It bypasses several metabolic steps in the body and better binds thymidylate synthase with FdUMP, a metabolite of the drug fluorouracil.

==Patent issues== In March 2012, Merck & Cie of Switzerland, Pamlab LLC (maker of Metanx and Cerefolin, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the United States District Court for the Eastern District of Texas against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs' patents.<ref name=6patents>The six patents named were {{patent|US|5997915}}, {{patent|US|6011040}}, {{patent|US|6254904}}, {{patent|US|6673381}}, {{patent|US|7674490}} and {{patent|US|7172778}}.</ref> The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).<ref>{{cite news|title=Pernix Therapeutics' Subsidiary Macoven Pharmaceuticals, LLC Named in Suit by Merck, Pamlab, L.L.C. and Others for Alleged|url=https://www.bloomberg.com/apps/news?pid=conewsstory&tkr=MKGAF:US&sid=aVfdD6EGy6Nc|access-date=1 October 2012|newspaper=Bloomberg|date=6 March 2012}}</ref>

In September 2012, the same three plaintiffs filed a complaint requesting that the International Trade Commission begin a {{uscsub|19|1337|}} investigation of the same four defendants. The complaint states that Gnosis' "Extrafolic-S" and products which are made from it, infringe upon three of their patents: {{patent|US|5997915}}, {{patent|US|6673381}}, and {{patent|US|7172778}}.<ref name=gnosis337>{{cite web|last=Schweibenz |first=Eric W. | name-list-style = vanc |title=SAMSF, Merck, and Pamlab File New 337 Complaint Regarding Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein |url=http://www.oblon.com/samsf-merck-and-pamlab-file-new-337-complaint-regarding-certain-reduced-folate-nutraceutical-product |work=Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. |archive-url=https://archive.today/20130130195443/http://www.oblon.com/samsf-merck-and-pamlab-file-new-337-complaint-regarding-certain-reduced-folate-nutraceutical-product |archive-date= 30 January 2013 |date=2012-09-10 |url-status=dead }}</ref>

==Formulations== * Levomefolate calcium, a calcium salt of levomefolic acid is sold under the brand name '''Metafolin'''<ref>{{Cite web |title=Metafolin |url=https://www.emdmillipore.com/US/en/products/small-molecule-pharmaceuticals/bulk-api/folates/l-metafolin/Metafolin/okeb.qB.qsoAAAFp2m8bIm4h,nav |access-date=28 November 2022 |website=MilliporeSigma |quote=Metafolin® is our manufactured calcium salt of L-5-methyltetrahydrofolic or L-methylfolate. ... The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the US and Canada.}}</ref> and incorporated in '''Deplin'''.<ref>{{Cite web |department=For Healthcare Professionals |url=https://www.deplin.com/hcp |access-date=28 November 2022 |title=DEPLIN® |language=en-US}}</ref> * Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.<ref>{{Cite web |title=EnLyte with DeltaFolate |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e83b2dd3-a9a0-40bc-ade4-6cd4db433b06 |access-date=28 November 2022 |website=dailymed.nlm.nih.gov}}</ref> * Levomefolate calcium (a calcium salt of levomefolic acid) is manufactured as ''Cerebrofolate''.<ref>Malik M, HUSSAIN A AND HASHMI A,{{Cite journal |title=COMPARATIVE IN VITRO EVALUATION OF (6S)-5- METHYLTETRAHYDROFOLATE BRANDS: THE POST MARKET SURVEILLANCE FOR QUALITY ASSESSMENT |url=https://ijbpas.com/archive/archive-single-pdf/6008 |access-date=28 November 2022 |website=ijbpas.com|volume=12 |issue=12 |last1=Al |first1=Malik M. et }}</ref>

== See also == * 5,10-Methylenetetrahydrofolate * S-Adenosylmethionine (SAMe)

== References == <references />

== External links == *[http://www.fao.org/docrep/008/a0044e/a0044e05.htm#bm5.3 Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)] * {{cite journal | vauthors = Brockton NT | title = Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? | journal = Cancer Causes & Control | volume = 17 | issue = 8 | pages = 1005–16 | date = October 2006 | pmid = 16933051 | doi = 10.1007/s10552-006-0051-5 | s2cid = 20394873 }} * {{cite journal | vauthors = Stahl SM | title = Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent | journal = CNS Spectrums | volume = 12 | issue = 10 | pages = 739–44 | date = October 2007 | pmid = 17934378 | doi = 10.1017/S1092852900015418 | s2cid = 27000937 }}

Category:Folates Category:Coenzymes Category:Medical food Category:Patent case law