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General Description:

Levomefolic acid, identified by CAS number 31690-09-2, is a notable compound with significant therapeutic applications. Levomefolic acid (INN) is the metabolite of folic acid (Vitamin B9) and it is a predominant active form of folate found in foods and in the blood circulation, accounting for 98% of folates in human plasma . It is transported across the membranes including the blood-brain barrier into various tissues where it plays an essential role in the DNA synthesis, cysteine cycle and regulation of homocysteine, where it methylates homocysteine and forms methionine and tetrahydrofolate (THF). Levomefolate is approved as a food additive and is designated a GRAS (generally regarded as safe) compound . It is available commercially as a crystalline form of the calcium salt (Metafolin(R)), which has the stability required for use as a supplement . Supplementation of levomefolic acid is desired over folic acid due to reduced potential for masking vitamin B12 deficiency symptoms.

Indications:

This drug is primarily indicated for: For the treatment and prevention of folate deficiency and for use as an antidote against folic acid antagonists. Contained in oral contraceptives to reduce the risk of neural tube defects arising from folic acid deficiency for pregnant women who conceived during use or shortly after the discontinuation of the product. Being studied for use as a treatment for cardiovascular diseases and adjunct therapy for patients undergoing antidepressant pharmacotherapy . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Levomefolic acid undergoes metabolic processing primarily in: Levomefolic acid is further converted into tetrahydrofolate (THF) via the vitamin B12-dependent enzyme methionine synthase before effective polyglutamylation by folylpolyglutamate synthetase (FPG). Polyglumate forms of folic acids are more effective substrates for associated enzymes in folate-dependent reactions. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Levomefolic acid are crucial for its therapeutic efficacy: Absorbed in the proximal small intestines via the active proton-coupled folate transporter (PCFT) that transports both oxidized and reduced folic acids. Passive diffusion also occurs at the proximal and distal portions of the small intestines . A single oral dose of 906nmol of levomefolic acid in healthy females resulted in the mean peak plasma concentration of 39.4nmol/L . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Levomefolic acid is an important consideration for its dosing schedule: The mean elimination half-life is approximately 3 hours after 5mg of oral L-methylfolate, administered daily for 7 days . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Levomefolic acid exhibits a strong affinity for binding with plasma proteins: Approximately 56% bound to plasma proteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Levomefolic acid from the body primarily occurs through: Mainly eliminated through renal or fecal excretion. Small proportion of excreted levomefolic acid is in unchanged form as over 99% of tissue folate is in polyglutamate form. Some portions of levomefolic acid is secreted into bile. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Levomefolic acid is distributed throughout the body with a volume of distribution of: Circulates in its free form or loosely bound to plasma proteins. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Levomefolic acid exerts its therapeutic effects through: Levomefolic acid is an active metabolite of folic acid and a methyl group donor in one-carbon metabolism reactions. It regulates important cellular functions such as DNA biosynthesis, gene expression regulation, amino acid synthesis and metabolism, and myelin synthesis and repair. As a only form of folate that can cross the blood-brain barrier, it acts as a cofactor in the production of monoamine neurotransmitters such as dopamine, serotonin and norepinephrine . Levomefolic acid is also involved in red blood cell formation . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Levomefolic acid functions by: Levomefolic acid plays a critical role in methylating homocysteines into methionine by acting as a methyl donor in a reaction catalyzed by vitamine B12-dependent methionine synthase. Homocysteine must either be further metabolized via transulfuration to become cysteine, taurine, and glutathione via a B6-dependent process, or re-methylated to become methionine again. Methionine formed from remethylation of homocysteine by levomefolic acid forms the downstream metabolite S-adenosylmethionine (SAMe), which is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters . Studies suggest that high plasma levels of homocysteine is associated with increased incidences of arterial plaque formation . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Levomefolic acid belongs to the class of organic compounds known as tetrahydrofolic acids. These are heterocyclic compounds based on the 5,6,7,8-tetrahydropteroic acid skeleton conjugated with at least one L-glutamic acid unit, classified under the direct parent group Tetrahydrofolic acids. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Pteridines and derivatives class, specifically within the Pterins and derivatives subclass.

Categories:

Levomefolic acid is categorized under the following therapeutic classes: Amino Acids, Amino Acids, Acidic, Amino Acids, Dicarboxylic, Amino Acids, Peptides, and Proteins, Coenzymes, Enzymes and Coenzymes, Folic Acid and Derivatives, Heterocyclic Compounds, Fused-Ring, Pteridines, Pterins, Vitamin B Complex, Vitamins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Levomefolic acid include:

• Water Solubility: Approximately 0.3 mg/ml
• Boiling Point: 221