Levomefolic acid

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Levomefolic acid
Identifiers
CAS number134-35-0, 151533-22-1 (calcium salt)
PubChem444412, 15341110 (calcium salt)
ChemSpider388371
UNII8S95DH25XC YesY
KEGGD09353
MeSH5-methyltetrahydrofolate
ATC codeB03BB51
Jmol-3D imagesImage 1
Properties
Molecular formulaC20H25N7O6
Molar mass459.46 g mol−1
Pharmacology
Routes of
administration
oral, transdermal, subcutaneous
Legal status


OTC(US)

Pregnancy
category
N
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references
 
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Levomefolic acid
Identifiers
CAS number134-35-0, 151533-22-1 (calcium salt)
PubChem444412, 15341110 (calcium salt)
ChemSpider388371
UNII8S95DH25XC YesY
KEGGD09353
MeSH5-methyltetrahydrofolate
ATC codeB03BB51
Jmol-3D imagesImage 1
Properties
Molecular formulaC20H25N7O6
Molar mass459.46 g mol−1
Pharmacology
Routes of
administration
oral, transdermal, subcutaneous
Legal status


OTC(US)

Pregnancy
category
N
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Levomefolic acid (INN) (also known as 5-MTHF, l-methylfolate and 5-methyltetrahydrofolate) is the active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. The un-methylated form, folic acid (vitamin B9), is a form of folate found in a variety of foods and can be isolated or synthesized for use in nutritional supplements. Folic acid is metabolized in the body into levomefolic acid. Approximately 10% of Caucasian and Asian populations (homozygous TT) have 70% less activity in the enzymes needed to receive any benefit from folic acid.[1] Another 40% of the population (heterozygous CT) appear to convert only a limited amount of folic acid into levomefolic acid. They cannot fully process supplemental folic acid at RDA or higher dose levels.[citation needed] The remaining population do not have a known MTHFR polymorphism and can therefore metabolize folic acid more efficiently.

It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivate of tetrahydrofolate (THF, H4F). Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (5,10-CH2-THF, MTHF) and used to recycle homocysteine back to methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) also known as methionine synthase (MS).[2]

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease[3][4] and advanced cancers such as breast and colorectal cancers. It bypasses several metabolic steps in the body and better binds thymidylate synthase with fDump, a metabolite of the drug fluorouracil.

Levomefolate calcium, a calcium salt of levomefolic acid, is sold under the brand names Metafolin (a registered trademark of Merck KGaA) and Deplin (trademark of Pamlab, LLC).[5]

Commercial use[edit]

Commercial use of levomefolic acid in pharmaceutical products began in Europe in the early part of this decade[clarification needed] and have now[when?] appeared in the United States. Supplementation of folate/folic acid has potential to impact prenatal care, homocysteine management, and the treatment of depression, dementia and cardiovascular concerns.

5-MTHF is widely available as over-the-counter nutritional supplements or as pharmaceutical preparations.

Legal issues[edit]

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.[7] The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).[8]

In September 2012, the same three plaintiffs filed a complaint requesting that the International Trade Commission begin an 19 U.S.C. § 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: US 5997915 , US 6673381 , and US 7172778 .[9]

See also[edit]

References[edit]

  1. ^ Pietrzik, Klaus; Lynn Bailey and Barry Shane (2010). "Folic Acid and L-5-Methyltetrahydrofolate Comparison of Clinical Pharmacokinetics and Pharmacodynamics". Clinical Pharmacokinetics: 535–548. PMID 20608755. 
  2. ^ "5-methyltetrahydrofolate - Compound Summary", PubChem (NCBI), retrieved 2012-09-25 
  3. ^ Willems, Frank F; Boers GHJ, Blom HJ, Aengevaeren WRM, Verheugt FWA (March 2004). "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease". Br J Pharmacol (Nature Publishing Group) 145 (5): 825–830. doi:10.1038/sj.bjp.0705446. PMC 1574248. PMID 14769778.  >
  4. ^ Iris P Fohr, Reinhild Prinz-Langenohl, Anja Brönstrup, Anja M Bohlmann, Heinz Nau, Heiner K Berthold, and Klaus Pietrzik, IP; Prinz-Langenohl, R; Brönstrup, A; Bohlmann, AM; Nau, H; Berthold, HK; Pietrzik, K (2002). "5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women". Am J Clin Nutr (American Society for Clinical Nutrition) 75 (2): 275–282. PMID 11815318. 
  5. ^ Lakely, Susan. "RPH". L-Methylfolate. Retrieved 12 January 2012. 
  6. ^ Stahl, S. M. (2010). "Enhancing outcomes from major depression: Using antidepressant combination therapies with multifunctional pharmacologic mechanisms from the initiation of treatment". CNS spectrums 15 (2): 79–94. PMID 20414154.  edit
  7. ^ The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490  and US 7172778 .
  8. ^ "Pernix Therapeutics’ Subsidiary Macoven Pharmaceuticals, LLC Named in Suit by Merck, Pamlab, L.L.C. and Others for Alleged". Bloomberg. 6 March 2012. Retrieved 1 October 2012. 
  9. ^ Schweibenz, Eric W. (2012-09-10). "SAMSF, Merck, and Pamlab File New 337 Complaint Regarding Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein". Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P. Archived from the original on 1 October 2012. 

External links[edit]