| Levomefolic acid |
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IUPAC name
(2S)-2-[ [4-[(2-Amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl) methylamino]benzoyl]amino]pentanedioic acid
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Other names
Alfive
(5-Me-THFA, 5-Me-H4FA),
anion: 5-methyltetrahydrofolate (5-Me-THF, 5-Me-H4F), L-methylfolate
Metafolin, Extrafolate-S
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| Identifiers |
| CAS number |
134-35-0, 151533-22-1 (calcium salt) |
| PubChem |
444412, 15341110 (calcium salt) |
| ChemSpider |
388371 |
| UNII |
8S95DH25XC Y |
| KEGG |
D09353 |
| MeSH |
5-methyltetrahydrofolate |
| ATC code |
B03BB51 |
| Jmol-3D images |
Image 1 |
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O=C(O)[C@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C)CCC(=O)O
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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-/m1/s1
Key: ZNOVTXRBGFNYRX-ZGTCLIOFBZ
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| Properties |
| Molecular formula |
C20H25N7O6 |
| Molar mass |
459.46 g mol−1 |
| Pharmacology |
Routes of
administration |
oral, transdermal, subcutaneous |
| Legal status |
OTC(US)
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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]
Contents
- 1 Commercial use
- 2 Legal issues
- 3 See also
- 4 References
- 5 External links
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.
- Prenatal care: low folate status has been linked to neural tube defects, recurrent pregnancy loss, low birth weight and a variety of age-related high risk complications of pregnancy.
- Homocysteine management: elevated homocysteine is frequently linked to the presence of the MTHFR polymorphism.
- Depression: folate status has been linked to the performance of SSRI drugs. Many patients have required folate supplementation in order to adequately respond to standard treatment protocol.[6]
- Dementia: folate status has been linked to the efficacy of neural transmitters and cognitive performance. Only active, levomefolic acid can cross the blood brain barrier.
- Diabetic neuropathy: folate status has been shown to have a substantial impact upon wound care.
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]
- 5,10-Methylenetetrahydrofolate (5,10-CH2-THF, MTHF)
- 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR)
- Methylenetetrahydrofolate reductase (MTHFR)
- S-Adenosylmethionine (SAMe)
References[edit]
- ^ 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.
- ^ "5-methyltetrahydrofolate - Compound Summary", PubChem (NCBI), retrieved 2012-09-25
- ^ 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. >
- ^ 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.
- ^ Lakely, Susan. "RPH". L-Methylfolate. Retrieved 12 January 2012.
- ^ 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
- ^ The six patents named were US 5997915 , US 6011040 , US 6254904 , US 6673381 , US 7674490 and US 7172778 .
- ^ "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.
- ^ 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]
- CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)
- Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?
- Stahl, SM (October 2007). "Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent". CNS Spectrums 12 (10): 739–744. PMID 17934378.
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Vitamins (A11)
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| Fat soluble |
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A
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α-Carotene · β-Carotene · Retinol# · Tretinoin
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D
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D2 (Ergosterol, Ergocalciferol#) · D3 (7-Dehydrocholesterol, Previtamin D3, Cholecalciferol, 25-hydroxycholecalciferol, Calcitriol (1,25-dihydroxycholecalciferol), Calcitroic acid) · D4 (Dihydroergocalciferol) · D5 · D analogues (Alfacalcidol, Dihydrotachysterol, Calcipotriol, Tacalcitol, Paricalcitol)
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E
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Tocopherol (Alpha, Beta, Gamma, Delta) · Tocotrienol (Alpha, Beta, Gamma, Delta) · Tocofersolan
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K
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Naphthoquinone · Phylloquinone (K1) · Menaquinones (K2) · Menadione (K3)‡ · Menadiol (K4)
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| Water soluble |
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B
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B1 (Thiamine#) · B2 (Riboflavin#) · B3 (Niacin, Nicotinamide#) · B5 (Pantothenic acid, Dexpanthenol, Pantethine) · B6 (Pyridoxine#, Pyridoxal phosphate, Pyridoxamine) · B7 (Biotin) · B9 (Folic acid, Dihydrofolic acid, Folinic acid, L-methylfolate) · B12 (Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Cobamamide) · Choline
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C
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Ascorbic acid# · Dehydroascorbic acid
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| Combinations |
Multivitamins
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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noco, nuvi, sysi/epon, met
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