Levomefolic acid (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
, 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
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...
used at the cellular level for
DNA reproduction, the
cysteine cycle and the regulation of
homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...
. 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
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
(THF). THF is the immediate acceptor of one carbon unit for the synthesis of
thymidine
Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...
-DNA,
purine
Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
s (RNA and DNA) and methionine. The un-methylated form,
folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
(vitamin B
9), is a synthetic form of folate, and must undergo enzymatic reduction by
dihydrofolate reductase (DHFR) to become biologically active.
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
5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF.
As an intermediate in one-carbon metabolism, 5,10-CH2 ...
(MTHF) and used to recycle homocysteine back to methionine by
methionine synthase
Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms ...
(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
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
administration. Peak concentrations were found to be more than seven times higher than folic acid (129
ng/ml vs. 14.1 ng/ml).
Metabolism
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
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
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
Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleo ...
with
FdUMP, a metabolite of the drug
fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
.
Patent issues
In March 2012,
Merck & Cie of
Switzerland,
Pamlab
Alfasigma USA, Inc. (''formerly'' Pamlab) is an American medical food company, and a division of Alfasigma Group, of Bologna, Italy.
Alfasigma's base of operations is located in Covington, Louisiana.
History
The company entered the pharmaceu ...
LLC (maker of
Metanx
Metanx is a prescription medical food made by Alfasigma that contains L-methylfolate (as Metafolin, a calcium salt of vitamin B9), methylcobalamin (vitamin B12) and pyridoxal 5'-phosphate (vitamin B6). It is a vitamin B supplement. Metanx is i ...
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
The United States District Court for the Eastern District of Texas (in case citations, E.D. Tex.) is a federal court in the Fifth Circuit (except for patent claims and claims against the U.S. government under the Tucker Act, which are appealed to ...
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 six patents named were , , , , and .] 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
The United States International Trade Commission (USITC or I.T.C.) is an agency of the United States federal government that advises the legislative and executive branches on matters of trade. It is an independent, bipartisan entity that analyze ...
begin an 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: , , and .
Formulations
Levomefolate calcium, a calcium
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...
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
5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF.
As an intermediate in one-carbon metabolism, 5,10-CH2 ...
*
S-Adenosylmethionine (SAMe)
References
External links
CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)*
*
{{Vitamin
Folates
Coenzymes
Medical food
Patent case law