U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C20H25N7O6
Molecular Weight 459.4558
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LEVOMEFOLIC ACID

SMILES

CN1[C@@H](CNC2=CC=C(C=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O)CNC3=C1C(=O)NC(N)=N3

InChI

InChIKey=ZNOVTXRBGFNYRX-STQMWFEESA-N
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

HIDE SMILES / InChI

Molecular Formula C20H25N7O6
Molecular Weight 459.4558
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

For people with MTHFR gene variations, supplementing with the already activated form of folate (5-MTHF/5- METHYLTETRAHYDROFOLATE/LEVOMEFOLIC ACID) is far more effective in providing this form of folate than introducing the pre-converted form to the body through typical folate supplements. L-Methylfolate (5-MTHF) supplements provide the active form of folate naturally present in the body and available for biological action. 5-MTHF—the “active” form of folate that is able to pass the blood brain barrier. However, without a properly functioning methylenetetrahydrofolate reductase, MTHFR this conversion cannot take place and folate is not converted to forms that can cross the blood brain barrier. That is where 5-MTHF supplements come in. Levomefolate calcium is structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9. Mean baseline concentrations of about 15 nmol/L are reached in populations without folate food fortification under normal nutritional conditions. Orally administered levomefolate calcium is absorbed and is incorporated into the body folate pool. Peak plasma concentrations of about 50 nmol/L above baseline are reached within 0.5 – 1.5 hours after single oral administration of 0.451 mg levomefolate calcium. Steady state conditions for total folate in plasma after intake of 0.451 mg levomefolate calcium. In red blood cells, achievement of steady state is delayed due to the long lifespan of red blood cells of about 120 days. Levomefolate calcium is a part of contraceptive tablets: SAFYRA. Safyral is an estrogen/progestin COC (Combined Oral Contraceptive) containing a folate, indicated for use by women to: prevent pregnancy and raise folate levels in women who choose to use an oral contraceptive for contraception. COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Approval Year

Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Preventing
SAFYRAL

Approved Use

1.1 Oral Contraceptive: Safyral is indicated for use by women to prevent pregnancy. 1.2 Folate Supplementation Safyral is indicated in women who choose to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product.

Launch Date

2010
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
57.7 nM
0.451 mg single, oral
dose: 0.451 mg
route of administration: Oral
experiment type: SINGLE
co-administered: ETHINYL ESTRADIOL
L-5-METHYLTETRAHYDROFOLATE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
370 nM × h
0.451 mg single, oral
dose: 0.451 mg
route of administration: Oral
experiment type: SINGLE
co-administered: ETHINYL ESTRADIOL
L-5-METHYLTETRAHYDROFOLATE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
5.5 h
0.451 mg single, oral
dose: 0.451 mg
route of administration: Oral
experiment type: SINGLE
co-administered: ETHINYL ESTRADIOL
L-5-METHYLTETRAHYDROFOLATE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
44%
0.451 mg single, oral
dose: 0.451 mg
route of administration: Oral
experiment type: SINGLE
co-administered: ETHINYL ESTRADIOL
L-5-METHYLTETRAHYDROFOLATE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency.
2004-09-15
Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells.
2004-09
Placental folate transport and binding are not impaired in pregnancies complicated by fetal growth restriction.
2004-07
Mutations of the MTHFR gene (428C>T and [458G>T+459C>T]) markedly decrease MTHFR enzyme activity.
2004-06
Methionine metabolism in plants: chloroplasts are autonomous for de novo methionine synthesis and can import S-adenosylmethionine from the cytosol.
2004-05-21
The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma.
2004-05-17
Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: the pleiotropic effects of folate supplementation.
2004-05-10
A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro.
2004-04-29
Hyperproliferation of homocysteine-treated colon cancer cells is reversed by folate and 5-methyltetrahydrofolate.
2004-04
The C677 mutation in methylene tetrahydrofolate reductase gene: correlation with uric acid and cardiovascular risk factors in elderly Korean men.
2004-04
Quantitative evaluation of the drug-drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier.
2004-04
5-Methyltetrahydrofolic acid and folic acid measured in plasma with liquid chromatography tandem mass spectrometry: applications to folate absorption and metabolism.
2004-03-15
Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease.
2004-03
Folic acid rescues nitric oxide-induced neural tube closure defects.
2004-03
Sodium-dependent methotrexate carrier-1 is expressed in rat kidney: cloning and functional characterization.
2004-03
Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications.
2004-02-17
Comparative study on pressure and temperature stability of 5-methyltetrahydrofolic acid in model systems and in food products.
2004-02-11
Solid-phase extraction-electrospray ionization mass spectrometry for the quantification of folate in human plasma or serum.
2004-02-01
Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients.
2004-02
Folate, homocysteine, endothelial function and cardiovascular disease.
2004-02
Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay.
2004-02
Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms: relationships with 5-fluorouracil sensitivity.
2004-01-26
Red cell N5-methyltetrahydrofolate concentrations and C677T methylenetetrahydrofolate reductase genotype in patients with stroke.
2004-01
Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore.
2003-12-18
Cobalamin-dependent methionine synthase: probing the role of the axial base in catalysis of methyl transfer between methyltetrahydrofolate and exogenous cob(I)alamin or cob(I)inamide.
2003-12-16
Dietary prevention of post-angioplasty restenosis. From illusion and disillusion to pragmatism.
2003-12
Thrombophilia and pregnancy.
2003-11-14
Age dependence of the influence of methylenetetrahydrofolate reductase genotype on plasma homocysteine level.
2003-11-01
Folate improves endothelial function in patients with coronary heart disease.
2003-11
Hyperhomocystinemia in children with inflammatory bowel disease.
2003-11
Regulation of S-adenosylmethionine levels in Saccharomyces cerevisiae.
2003-10-31
Characterization of a pseudogene for murine methylenetetrahydrofolate reductase.
2003-10
Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome: a new phenotype.
2003-09-09
Reduced folate transport to the CNS in female Rett patients.
2003-08-26
Uptake of 5-methyltetrahydrofolate into PC-3 human prostate cancer cells is carrier-mediated.
2003-08
Antisense modulation of the coding or regulatory sequence of the folate receptor (folate binding protein-1) in mouse embryos leads to neural tube defects.
2003-07
Residues 45 and 404 in the murine reduced folate carrier may interact to alter carrier binding and mobility.
2003-06-27
A mass spectrometric validated high-performance liquid chromatography procedure for the determination of folates in foods.
2003-06-18
Analysis of the human folate receptor beta gene for an association with neural tube defects.
2003-06
Model studies on the stability of folic acid and 5-methyltetrahydrofolic acid degradation during thermal treatment in combination with high hydrostatic pressure.
2003-05-21
Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy.
2003-05
Specific and sensitive quantification of folate vitamers in foods by stable isotope dilution assays using high-performance liquid chromatography-tandem mass spectrometry.
2003-05
Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation.
2003-05
Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?
2003-04-01
Determination of 5-methyltetrahydrofolic acid and folic acid in citrus juices using stable isotope dilution-mass spectrometry.
2003-02-26
Transport of 5-formyltetrahydrofolate into primary cultured cerebellar granule cells.
2003-02-07
Affinity extraction combined with stable isotope dilution LC/MS for the determination of 5-methyltetrahydrofolate in human plasma.
2003-02-01
Transport of 5-formyltetrahydrofolate into primary cultured rat astrocytes.
2003-02-01
Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype.
2003-02
Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution.
2002-12
Patents

Sample Use Guides

Take one tablet daily by mouth at the same time every day
Route of Administration: Oral
neural stem cells (NSCs) were exposed to folic acid or 5-methyltetrahydrofolate (5-MTHF) (0-200 μmol/L) for 24, 48 or 72 h
Substance Class Chemical
Created
by admin
on Mon Mar 31 18:30:24 GMT 2025
Edited
by admin
on Mon Mar 31 18:30:24 GMT 2025
Record UNII
8S95DH25XC
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
L-METHYLFOLATE
VANDF  
Preferred Name English
LEVOMEFOLIC ACID
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
N-(4-((((6S)-2-AMINO-5-METHYL-4-OXO-1,4,5,6,7,8-HEXAHYDROPTERIDIN-6- YL)METHYL)AMINO)BENZOYL)-L-GLUTAMIC ACID
Systematic Name English
L-5-MTHF
Common Name English
(6S)-5-methyltetrahydrofolate [WHO-DD]
Common Name English
(6S)-5-METHYLTETRAHYDROFOLATE
WHO-DD  
Common Name English
5- METHYLTETRAHYDROFOLATE
Common Name English
5-METHYL-(6S)-TETRAHYDROFOLIC ACID
Common Name English
LEVOMEFOLATE
VANDF  
Common Name English
Levomefolic acid [WHO-DD]
Common Name English
levomefolic acid [INN]
Common Name English
LEVOMEFOLATE [VANDF]
Common Name English
5-MTHF
Common Name English
LEVOMEFOLINIC ACID
Common Name English
L-METHYLFOLATE [VANDF]
Common Name English
LMSR
Common Name English
L-GLUTAMIC ACID, N-(4-((((6S)-2-AMINO-3,4,5,6,7,8-HEXAHYDRO-5-METHYL-4-OXO-6- PTERIDINYL)METHYL)AMINO)BENZOYL)-
Common Name English
LEVOMEFOLIC ACID [USAN]
Common Name English
Code System Code Type Description
FDA UNII
8S95DH25XC
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
DRUG CENTRAL
4621
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
WIKIPEDIA
LEVOMEFOLIC ACID
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
PUBCHEM
135398561
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
CAS
31690-09-2
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
INN
8917
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
DAILYMED
8S95DH25XC
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
NCI_THESAURUS
C81119
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
SMS_ID
100000127631
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
DRUG BANK
DB11256
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
EVMPD
SUB33688
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
RXCUI
1025342
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
CHEBI
18608
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
EPA CompTox
DTXSID00185583
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
RXCUI
1592257
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
ALTERNATIVE
NCI_THESAURUS
C1505
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
CONCEPT Dietary Supplement
USAN
TT-129
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
ChEMBL
CHEMBL1231574
Created by admin on Mon Mar 31 18:30:24 GMT 2025 , Edited by admin on Mon Mar 31 18:30:24 GMT 2025
PRIMARY
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