Levomefolic acid/ja

Levomefolic acid/ja

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 (L-5-Me-THFA, L-5-Me-H4FA), anion: L-5-methyltetrahydrofolate (L-5-Me-THF, L-5-Me-H4F), L-methylfolate Metafolin
Identifiers
CAS Number	31690-09-2 151533-22-1 (calcium salt)
3D model (JSmol)	Interactive image
ChEBI	CHEBI:136009
ChemSpider	392351
KEGG	D09353
MeSH	5-methyltetrahydrofolate
PubChem CID	444412 15341110 (calcium salt)
UNII	8S95DH25XC Y A9R10K3F2F (calcium salt) Y
InChI 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
SMILES CN1c2c([nH]c(nc2=O)N)NC[C@@H]1CNc3ccc(cc3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Properties
Chemical formula	C20H25N7O6
Molar mass	459.463 g·mol−1
Pharmacology
ATC code	B03BB51 (WHO)
Routes of administration	oral, transdermal, subcutaneous
Legal status	US: OTC

レボメ葉酸（L-5-MTHF、L-methylfolate、L-5-methyltetrahydrofolate、（6S）-5-methyltetrahydrofolateとしても知られる、 および(6S)-5-メチルテトラヒドロ葉酸、(6S)-5-MTHF）は、細胞レベルでDNAの再生産、システインサイクル、およびホモシステインの制御に用いられる葉酸の主要な生物学的に活性な形態である。葉酸はまた、血液脳関門を通過して循環し、膜を通過して組織に輸送される。細胞内では、L-メチル葉酸は、メチオニンとテトラヒドロ葉酸（THF）を形成するためにホモシステインのメチル化で使用される。THFは、チミジン-DNA、プリン（RNAおよびDNA）、およびメチオニンの合成のための1炭素単位の即時受容体である。メチル化されていない葉酸（ビタミンB₉）は葉酸の合成形態であり、生物学的に活性になるためにはジヒドロ葉酸還元酵素（DHFR）による酵素的還元を受けなければならない。

ポリグルタミル化された食事性葉酸から小腸の吸収細胞で合成される。テトラヒドロ葉酸のメチル化誘導体である。

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).

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).

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

Medical uses

Major depressive disorder

Research suggests that levomefolic acid (L-methylfolate) taken with a first-line antidepressant provides a modest adjunctive antidepressant effect for individuals who do not respond or have only a partial therapeutic response to SSRI or SNRI medication, and might be a more cost-effective adjunctive agent than second-generation antipsychotics.

Cardiovascular disease and cancer

Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease 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.

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

In September 2012, the same three plaintiffs filed a complaint requesting that the International Trade Commission begin a 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 .

Formulations

Levomefolate calcium, a calcium salt of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. Levomefolate magnesium is a magnesium salt of levomefolic acid, manufactured as DeltaFolate, a primary ingredient in EnLyte.

See also

• 5,10-Methylenetetrahydrofolate
• S-Adenosylmethionine (SAMe)

External links

• Calcium L5-methyltetrahydrofolate (L-5-MTHF-Ca)
• Brockton NT (October 2006). "Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?". Cancer Causes & Control. 17 (8): 1005–16. doi:10.1007/s10552-006-0051-5. PMID 16933051. S2CID 20394873.
• Stahl SM (October 2007). "Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent". CNS Spectrums. 12 (10): 739–44. doi:10.1017/S1092852900015418. PMID 17934378. S2CID 27000937.