Levomefolic acid

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Levomefolic acid
5-Methyltetrahydrofolate.png
Names
IUPAC name
(2S)-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid
Other names
Alfive
(5-Me-THFA, 5-Me-H4FA),
anion: 5-methyltetrahydrofolate (5-Me-THF, 5-Me-H4F), L-methylfolate
Metafolin, Extrafolate-S
Identifiers
134-35-0
151533-22-1 (calcium salt)
ChemSpider 392351
Jmol 3D model Interactive image
KEGG D09353
MeSH 5-methyltetrahydrofolate
PubChem 444412
15341110 (calcium salt)
UNII 8S95DH25XC YesY
  • InChI=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
    Key: ZNOVTXRBGFNYRX-STQMWFEESA-N
  • 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
    Key: ZNOVTXRBGFNYRX-STQMWFEEBP
  • CN1c2c([nH]c(nc2=O)N)NC[C@@H]1CNc3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Properties
C20H25N7O6
Molar mass 459.46 g·mol−1
Pharmacology
ATC code B03BB51
Legal status
oral, transdermal, subcutaneous
Vapor pressure {{{value}}}
Except where otherwise noted, 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 and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folic acid 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 units 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 methylenetetrahydrofolate reductase (MTHFR) to become biologically active.[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 MTHFR from 5,10-methylenetetrahydrofolate (MTHF) and used to recycle homocysteine back to methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) also known as methionine synthase (MS).[2]

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).[3]

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease[4][5] and advanced cancers such as breast and colorectal cancers[citation needed]. 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).[6] Methyl folate can be bought at online stores or in some chemists though without a prescription.

Metabolism

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: mehtylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAME: S-adenosyl-L-methionine; THF: tetrahydrofolate.

Legal 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.[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

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ http://intetlab.com/site/products/Cerefolin-NAC_package-insert_%204-26-10.pdf
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490  and US 7172778 .
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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