Reduced Folates

Chemical Division




The Vitamin Folic Acid 1, which occurs ubiquitously in nature, especially in yeast, liver and green vegetables, is not active as such in the mammalian body, but is reduced enzymatically to 5,6,7,8-Tetrahydrofolic Acid 2: this coenzyme form acts as a carrier for various one-carbon units. These endogenous reduced folates participate in important metabolic reactions like the de novo purine and pyrimidine biosynthesis and also the biosynthesis of proteinogenic amino acids: for example 5-Methyl-tetrahydrofolic acid 3 acts as the methyl-group donor in the biosynthesis of Methionine.


Nutritional Use

Folate deficiencies can typically occur in several different situations, like:
inadequate nutrition, absorption or utilization (i.e after treatment with high doses of the antimetabolite Methotrexate) or increased requirements (pregnancy, lactation, malignancy). The consequences of a folate deficiency can be: birth defects (i.e. “spina bifida”), megaloblastic anemia, some types of depression,….. (see below).
In all cases of deficiency or to prevent deficiency, the folate pool can be advantageously replenished by oral administration of a reduced folate, like Calcium Folinate 4
(see for example: “Development of Human Folate Deficiency”, V.Herbert et al., Folic Acid Metabolism in Human Health an Disease, 195-210. (1990)).


Oncological Use

Two main uses of reduced folates in the oncological field can be cited:


  • as antidotes to Folic Acid antagonists, such as Methotrexate (“rescue therapy”), used in the treatment of certain neoplastic diseases, psoriasis and rheumatoid arthritis.
  • as biochemical modulators enhancing the cytotoxic activity of 5-Fluorouracil. This is a widely used therapy, especially in the treatment of colorectal cancer.


Pharmacologically most relevant reduced folates

Reduced Folate


  • Calcium Folinate
  • Calcium Levofolinate
  • 5-Methyl-tetrahydrofolic acid calcium salt
  • (6S)- 5-Methyl-tetrahydrofolic acid calcium salt
  • Folinic acid
  • (6S)-Folinic acid
  • Sodium Folinate
  • (6S)-Sodium Folinate
  • (6RS)-Calcium Folinate
  • (6S)-Calcium Folinate
  • (6RS)-N5-Me-THF.Ca2+
  • (6S)-N5-Me-THF.Ca2+
  • (6RS)-Folinic Acid
  • (6RS)-Sodium Folinate


Use of reduced folates as nutritional or therapeutical agents

The most common uses of reduced folates are:


  • Rescue therapy after high dose Methotrexate (oncological use or treatment of rheumatoid arthritis) 1)
  • Combination with 5-Fluorouracil and Oxaliplatin (oncological use) 2),11)
  • Prevention of neural tube defects (nutritional use) 3),9)
  • Treatment of folate deficiencies like megaloblastic anemia
  • Treatment of Dihydropteridinreductase deficiency 4)
  • Prevention and/or treatment of cardiovascular disease derived from high total serum homocysteine concentrations 5), 6),9),12)
  • Prevention and/or treatment of Alzheimer disease related to high total serum homocysteine concentrations 6),9)
  • Improvement of endothelial function in coronary artery disease via a mechanism independent from homocysteine lowering 5)
  • Prevention of colorectal cancer 7)
  • Treatment of depressive disorders 8)
  • Treatment of cerebral folate deficiency 10)



  1. (a) J.H.Schornagel, J.G.McVie, "The clinical Pharmacology of Methotrexate", Cancer treatment reviews, 10, (1983), 53. (b) S.L.Whittle, R.A.Hughes, “Folate supplementation and methotrexate treatment in rheumatoid arthritis”, Rheumatology, 43, no.3, (2004), 267-271
  2. (a) Y.M.Rustum, "Fluoropyrimidines in Cancer Therapy", (Series: Cancer Drug Discovery and Development), Humana Press (2002). (b) Oxaliplatin plus high dose folinic acid and 5-FU i.v. bolus (OXAFAFU) versus irinotecan plus high dose folinic acid and 5-FU i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial.
  3. Geneva Foundation of Medical Education and Research: "Neural Tube Defects, Folic Acid". See:
  4. R.C.Woody, M.A.Brewster, C.Glasier, "Progressive intracranial calcification in dihydropteridine reductase deficiency prior to folinic therapy", Neurology, 39, (1989),673-675.
  5. S.J.Moat, D.Lang, I.F.W.McDowell, Z.L.Clarke, A.K.Madhavan, M.J.Lewis, J.Goodfellow, "Folate, homocysteine, endothelial function and cardiovascular disease", Journal of Nutritional Biochemistry, 15, (2004), 64-79 and refs cited therein.
  6. (a) M.Gallucci, A.Zanardo, L.DeValentin, A.Vianello, "Homocysteine in Alzheimer Disease and Vascular Dementia",Arch.Gerontol.Geriatr.,Suppl. 9, (2004), 195-200. (b) P.Quadri, C.Fragiacomo, R.Pezzati, E.Zanda, G.Forloni, M.Tettamanti, "Homocysteine, folate and vitamin B-12 in mild cognitive impairment, Alzheimer disease and vascular dementia", Am J Clin Nutr, 80, (2004), 114-22.
  7. Young-In Kim, "Folate, Colorectal Carcinogenesis and DNA Methylation: Lessons from Animal Studies", Environmental and Molecular Mutagenesis, 44, (2004), 10-25.
  8. M.J.Taylor, S.M.Carney, G.M.Goodwin, J.R.Geddes, "Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials", J Psychopharmacology, 18, (2004), 251-6.
  9. (a) S.W.Bailey et al., "Pharmacokinetics of oral folic acid compared to 5-Methyl-(6S)-tetrahydrofolate in human plasma",FASEB journal, Vol.19, nr.4, suppl. S, Part1, (2005), A52. and ibid. "Urinary folate excretion after oral doses of folic acid or 5-Methyl-6(S)-tetrahydrofolate in humans". (b) A.J.Wright et al., “Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortifications in the UK”, British Journal of Nutrition, (2007), 98, 667-675.
  10. P.Moretti et al., "Cerebral folate deficiency with developmental delay, autism and response to folinic acid", Neurology, Vol. 64, (2005), 1088-90.
  11. K.Farker et al., "Chronomodulated chemotherapy with oxaliplatin, 5-FU and sodium folinate in metastatic gastrointestinal cancer patients: analysis of non-hematological toxicity and patient characteristics in a pilot investigation", International Journal of Clinical Pharmacology and Therapeutics, Vol.44, (2006), 31-37.
  12. B.Akoglu et al., “The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo controlled study”, European Journal of Clinical Nutrition, Vol. 62, (2008), 796-801.