Advifolate - L-5-Methyltetrahydrofolate calcium salt [L-5-MTHF-Ca] [USP]

Advifolate Key Facts

Compliant to latest USP monograph; L Isomer: 95 to 102%; D isomer: NMT 1%

High purity product; Control on all impurities as per USP monograph

Realtime stability data - minimum 4 years of stability

EFSA recognises L-5-Methyltetrahydrofolate calcium salt as bioavailable source of folate and safe for use in infant and follow-on formula, babyfood and processed cereal-based food

Full technical support is available for method development and formulation development

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Background

L-5 Methyltetrahydrofolate Calcium is a source of folate and an alternative to folic acid. Folate (vitamin B9) is the term used to refer to a family of water-soluble B-vitamins which serve a vital role in reactions required for normal cell metabolism and regulation, and in the synthesis of DNA and RNA methionine regulation (Bailey & Gregory, 1999). Maintaining adequate folate levels vital at all stages of life however it is especially important during gestation and infancy, with folate deficiency being associated with an increased risk for neural tube defects, certain chronic diseases and cancer (Shrubsole et al., 2001; Robinson et al., 1998; Laurence et al., 1981). Folate is an essential vitamin, and cannot be synthesized by the body and must therefore be obtained through the diet or supplementation. Dietary folate naturally occurs in foods such as green leafy vegetables, legumes, egg yolk and liver, while folic acid is the synthetic form.

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Folic Acid Vs Folate

To become metabolically active, folic acid must be converted to dihydrofolate and then tetrahydrofolate which is subsequently converted to the biologically active L-5-Methyltetrahydrofolate by an enzyme called methylenetetrahydrofolate reductase. However, many individuals have a genetic polymorphism in which their methylenetetrahydrofolate reductase enzyme is less active, meaning that they are unable to convert folic acid to L-5-Methyltetrahydrofolate (Greenberg et al., 2011). This poses as a problem for folic acid supplementation, as it has been found that in people with this type of polymorphism, folic acid is unable to raise plasma L-5-Methyltetrahydrofolate levels (Greenberg et al., 2011). Calcium salt of L-5 Methyltetrahydrofolate has a great stability profile and it has been shown to be a superior supplement to folic acid as it reduces the potential for masking haematological symptoms of vitamin B12 deficiency (Savage & Lindenbaum, 1994), reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism, as well as reducing the potential negative effects of folic acid in peripheral circulation (Scaglione & Panzavolta, 2014; Pietrzik et al., 2010).

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Chemistry

L-5 Methyltetrahydrofolate Calcium

CAS – 151533-22-1
Molecular Formula – C20H23CaN7O6.xH2O; C20H23CaN7O6 (anhydrous form)
Molecular Weight – 497.5 g/mol
IUPAC - N-[4-[[(2-Amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl) methyl]amino]benzoyl]-L-glutamic acid

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Folate and Health

Folate deficiency can be caused by many factors including dietary insufficiency, malabsorption, medication or an increase in requirements based on physiological conditions (for example, during pregnancy). This deficiency has been associated with an increased risk of several chronic diseases such as cardiovascular disease, cancer and cognitive dysfunction (Ebara, 2017). Folate deficiency has also led to other ailments such as ulcerations on the tongue, changes in skin, hair, or fingernail pigmentation, gastrointestinal symptoms, and elevated blood homocysteine concentrations (Bailey & Caudill, 2012; Carmel, 2005; Ho et al., 2011).

Cancer

Low folate status has been associated with numerous cancers such as colorectal, breast and prostate cancer (Chen et al., 2009). Folate intake has also been associated with a protective effect for some cancers including cancers of the bladder (He & Shui, 2014), pancreatic (Lin et al., 2013), oesophageal (Tio et al., 2014) and pharyngeal (Galeone et al., 2015).

Autism Spectrum Disorder

There is evidence that suggests increasing folate intake periconceptionally may reduce the risk of Autism Spectrum Disorder (ASD) from prenatal exposure to certain drugs and toxic chemicals (Roffman, 2018; DeVilbiss et al., 2015).

Cardiovascular Disease

While increased levels of folate do not directly decrease the risk of cardiovascular disease, elevated homocysteine levels have been associated with an increased risk of cardiovascular disease (Bailey & Caudill, 2012) and folate, along with other B vitamins have been shown to be involved in homocysteine metabolism, decreasing homocysteine levels and therefore could indirectly reduce cardiovascular disease risk.

Cognitive Decline, Dementia and Alzheimer’s disease

Elevated homocysteine levels have also been observed to correlated to an increased incidence of Alzheimer’s disease as well as dementia (Ho et al., 2011). There have also been numerous observational studies that have found correlations between low serum folate concentrations and a higher risk of dementia and Alzheimer’s disease, as well as poor cognitive function (Kim et al., 2018; Hooshmand et al., 2011; Smith & Refsum, 2016).

Depression

Studies have found a link between low folate status and depression and a poor response to antidepressants (Huang et al., 2018; Gougeon et al., 2015).

Neural tube defects

Neural tube defects result in the malformation of the spine (spina bifida), skill, and brain. Folate is especially important during phases of rapid cell growth due to it playing a role in the synthesis of DNA and other critical cell components (Lamers, 2011), with numerous clinical trials demonstrating the importance of supplementation periconceptionally to help prevent neural tube defects (Wilson et al., 2007; Pitkin, 2007; Scott, 2001).

Interactions with Medications

Methotrexate is used to treat rheumatoid arthritis. However, Methotrexate directly inhibits target enzymes of the folate pathway, reducing plasma folate levels (Liu et al., 2018). Therefore, not only is increasing folate levels through supplementation in individuals being treated with Methotrexate very important for general health, but it has also been shown to reduce the incidence of hepatoxicity, gastrointestinal side-effects and patient withdrawal in these individuals (Liu et al., 2018).

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EFSA Approved Health Claims

• Folate contributes to normal psychological function (2010;8(10): 1760).
• Folate contributes to the normal function of the immune function (2009;7(9): 1213).
• Folate contributes to the reduction of tiredness and fatigue (2010;8(10);1760).
• Folate has a role in the process of cell division (2009;7(0): 1213; 2010;8(10):1760)
• Folate contributes to normal homocysteine metabolism (2009;7(9):1213).
• Folate contributes to normal blood formation (2009;7(9):1213).
• Folate contributes to normal amino acid synthesis (2010;8(10):1760).
• Folate contributes to material tissue growth during pregnancy (2009; 7(9):1213).

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Trademark

Advifolate is a trademark of Vita Actives, EU trademark number 018526656.

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References

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18. Liu, L., Liu, S., Wang, C., Guan, W., Zhang, Y., Hu, W., Zhang, L., He, Y., Lu, J., Li, T., Liu, X., Xuan, Y. and Wang, P., 2018. Folate Supplementation for Methotrexate Therapy in Patients with Rheumatoid Arthritis. JCR: Journal of Clinical Rheumatology, 25(5), pp.197-202.
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21. Robinson, K., Arheart, K., Refsum, H., Brattström, L., Boers, G., Ueland, P., Rubba, P., Palma-Reis, R., Meleady, R., Daly, L., Witteman, J. and Graham, I., 1998. Low Circulating Folate and Vitamin B6Concentrations. Circulation, 97(5), pp.437-443.
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24. Scaglione, F. and Panzavolta, G., 2014. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica, 44(5), pp.480-488.
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26. Shrubsole, M., Din, F., Dai, Q., Shu, X., Potter, J., Herbert, J., Gao, Y. and Zheng, W., 2001. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res., 61(19), pp.7136-7141.
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28. Tio, M., Andrici, J., Cox, M. and Eslick, G., 2014. Folate intake and the risk of upper gastrointestinal cancers: A systematic review and meta-analysis. Journal of Gastroenterology and Hepatology, 29(2), pp.250-258.
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30. Wilson, R., Désilets, V., Wyatt, P., Langlois, S., Gagnon, A., Allen, V., Blight, C., Johnson, J., Audibert, F., Brock, J., Koren, G., Goh, I., Nguyen, P. and Kapur, B., 2007. Pre-conceptional Vitamin/Folic Acid Supplementation 2007: The Use of Folic Acid in Combination with a Multivitamin Supplement for the Prevention of Neural Tube Defects and Other Congenital Anomalies. Journal of Obstetrics and Gynaecology Canada, 29(12), pp.1003-1013.