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Folic Acid and L-5-Methyltetrahydrofolate

Comparison of Clinical Pharmacokinetics and Pharmacodynamics

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Abstract

There is a large body of evidence to suggest that improving periconceptional folate status reduces the risk of neonatal neural tube defects. Thus increased folate intake is now recommended before and during the early stages of pregnancy, through folic acid supplements or fortified foods. Furthermore, there is growing evidence that folic acid may have a role in the prevention of other diseases, including dementia and certain types of cancer.

Folic acid is a synthetic form of the vitamin, which is only found in fortified foods, supplements and pharmaceuticals. It lacks coenzyme activity and must be reduced to the metabolically active tetrahydrofolate form within the cell. L-5-methyl-tetrahydrofolate (L-5-methyl-THF) is the predominant form of dietary folate and the only species normally found in the circulation, and hence it is the folate that is normally transported into peripheral tissues to be used for cellular metabolism. L-5-methyl-THF is also available commercially as a crystalline form of the calcium salt (Metafolin®), which has the stability required for use as a supplement.

Studies comparing L-5-methyl-THF and folic acid have found that the two compounds have comparable physiological activity, bioavailability and absorption at equimolar doses. Bioavailability studies have provided strong evidence that L-5-methyl-THF is at least as effective as folic acid in improving folate status, as measured by blood concentrations of folate and by functional indicators of folate status, such as plasma homocysteine.

Intake of L-5-methyl-THF may have advantages over intake of folic acid. First, the potential for masking the haematological symptoms of vitamin B12 deficiency may be reduced with L-5-methyl-THF. Second, L-5-methyl-THF may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase.

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References

  1. Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med 2009; 11: e4

    Article  PubMed  Google Scholar 

  2. Schmitz JC, Stuart RK, Priest DG. Disposition of folic acid and its metabolites: a comparison with leucovorin. Clin Pharmacol Ther 1994; 55: 501–8

    Article  PubMed  CAS  Google Scholar 

  3. Lucock M, Wild J, Smithells R, et al. Biotransformation of pteroyl-monoglutamic acid during absorption: implications of Michaelis-Menten kinetics. Eur J Clin Nutr 1989; 43(9): 631–5

    PubMed  CAS  Google Scholar 

  4. Kelly P, McPartlin J, Goggins M, et al. Unmetabolized folic acid in serum: acute studiesin subjects consuming fortified food and supplements. Am J Clin Nutr 1997; 65(6): 1790–5

    PubMed  CAS  Google Scholar 

  5. Stern LL, Bagley PJ, Rosenberg IH, et al. Conversion of 5-formyl-tetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylene-tetrahydrofolate reductase gene. J Nutr 2000; 130(9): 2238–42

    PubMed  CAS  Google Scholar 

  6. Perry J, Chanarin I. Intestinal absorption of reduced folate compoundsin man. Br J Haematol 1970; 18(3): 329–39

    Article  PubMed  CAS  Google Scholar 

  7. Pentieva K, McNulty H, Reichert R, et al. The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr 2004; 134(3): 580–5

    PubMed  CAS  Google Scholar 

  8. Prinz-Langenohl R, Lamers Y, Moser R, et al. Effect of folic acid preload on the bioequivalence of [6S]-5-methyltetrahydrofolate and folic acid in healthy volunteers [abstract no. 169-P]. J Inherit Metab Dis 2003; 26 Suppl. 1: 124

    Google Scholar 

  9. Melse-Boonstra A, Verhoef P, West C. Quantifying folate bioavailability: a critical appraisal of methods. Curr Opin Clin Nutr Metab Care 2004; 7(5): 539–45

    Article  PubMed  Google Scholar 

  10. Fohr IP, Prinz-Langenohl R, Brönstrup A, et al. 5,10-Methylenetetrahy-drofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 2002; 75(2): 275–82

    PubMed  CAS  Google Scholar 

  11. Lamers Y, Prinz-Langenohl R, Moser R, et al. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homo-cysteine concentrations in healthy women. Am J Clin Nutr 2004; 79(3): 473–8

    PubMed  CAS  Google Scholar 

  12. Houghton LA, Sherwood KL, Pawlosky R, et al. [6S]-5-Methyltetrahy-drofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am J Clin Nutr 2006; 83(4): 842–50

    PubMed  CAS  Google Scholar 

  13. De Meer K, Smulders YM, Dainty JR, et al. [6S]5-methyltetrahydrofolate or folic acid supplementation and absorption and initial elimination of folate in young and middle-aged adults. Eur J Clin Nutr 2005; 59(12): 1409–16

    Article  PubMed  Google Scholar 

  14. Bhandari SD, Gregory JF. Folic acid, 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate exhibit equivalent intestinal absorption, metabolism and in vivo kinetics in rats. J Nutr 1992; 122: 1847–54

    PubMed  CAS  Google Scholar 

  15. Gregory JF, Bhandari SD, Bailey LB, et al. Relative bioavailability of deuterium-labeled monoglutamyl tetrahydrofolates and folic acid in human subjects. Am J Clin Nutr 1992; 55: 1147–53

    PubMed  CAS  Google Scholar 

  16. Wright JA, Finglas PM, Dainty JR, et al. Differential kinetic behavior and distribution for pteroylglutamic acid and reduced folates:a revised hypothesis of the primary site of PteGlu metabolism in humans. J Nutr 2005; 135: 619–23

    PubMed  CAS  Google Scholar 

  17. Sirotnak FM, Tolner B. Carrier mediated membrane transport of folates in mammalian cells. Ann Rev Nutr 1999; 19: 91–122

    Article  CAS  Google Scholar 

  18. Chiao JH, Roy K, Tolner B, et al. RFC-1 gene expression regulates folate absorption in mouse small intestine. J Biol Chem 1997; 272(17): 11165–70

    Article  PubMed  CAS  Google Scholar 

  19. Chen L, Qi H, Korenberg J, et al. Purification and properties of human cyto-solic folylpolyglutamate synthetase and organization, localization and differential splicing of its gene. J Biol Chem 1996; 271: 13077–87

    Article  PubMed  CAS  Google Scholar 

  20. Green JM, Ballou DP, Matthews RG. Examination of the role of methylene-tetrahydrofolate reductase in incorporation of methyltetrahydrofolate into cellular metabolism. FASEB J 1988; 2: 42–7

    PubMed  CAS  Google Scholar 

  21. Shane B. Folylpolyglutamate synthesis and role in the regulation of one carbon metabolism. Vit Horm 1989; 45: 263–335

    Article  CAS  Google Scholar 

  22. Shane B. Folate, vitamin B12 and vitamin B6. In: Stipanuk MH, editor. Biochemical and physiological aspects of human nutrition. New York: WB Saunders Company, 2000: 483–518

    Google Scholar 

  23. Blakley RL. Dihydrofolate reductase. In: Blakley RL, Benkovic SJ, editors. Folates and pterins: chemistry and biochemistry of folates. Vol. 1. New York: Wiley, 1984: 191–244

    Google Scholar 

  24. Matthews RG, Ghose C, Green JM, et al. Folylpolyglutamates as substrates and inhibitors of folate-dependent enzymes. In: Weber G, editor. Advances in enzyme regulation. Vol. 26. Oxford: Pergamon Press, 1987; 157–71

    Google Scholar 

  25. Gregory III JF, Cuskelly GJ, Shane B, et al. Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homo-cysteine remethylation, and transsulfuration processes in human one-carbon metabolism. Am J Clin Nutr 2000; 72(6): 1535–41

    PubMed  CAS  Google Scholar 

  26. Woeller CF, Anderson DD, Szebenyi DME, et al. Evidence for SUMO-dependent nuclear location of the thymidylate biosynthesis pathway. J Biol Chem 2007; 282(24): 17623–31

    Article  PubMed  CAS  Google Scholar 

  27. Wolffe AP, Jones PL, Wade PA. DNA methylation. Proc Natl Acad Sci U S A 1999; 96: 5894–6

    Article  PubMed  CAS  Google Scholar 

  28. Gregory III JF, Williamson J, Liao JF, et al. Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools. J Nutr 1998; 128(11): 1896–906

    PubMed  CAS  Google Scholar 

  29. Suh JR, Herbig AK, Stover PJ. New perspectives on folate catabolism. Annu Rev Nutr 2001; 21: 255–82

    Article  PubMed  CAS  Google Scholar 

  30. Gregory III JF. Case study: folate bioavailability. J Nutr 2001; 131(4 Suppl.): 1376–82S

    Google Scholar 

  31. Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270(22): 2693–8

    Article  PubMed  CAS  Google Scholar 

  32. Tucker KL, Selhub J, Wilson PW, et al. Dietary intake pattern relates toplasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr 1996; 126(12): 3025–31

    PubMed  CAS  Google Scholar 

  33. Brouwer IA, van Dusseldorp M, West CE, et al. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 1999; 129(6): 1135–9

    PubMed  CAS  Google Scholar 

  34. Venn BJ, Green TJ, Moser R, et al. Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydro-folate and folic acid. J Nutr 2002; 132(11): 3353–5

    PubMed  CAS  Google Scholar 

  35. Venn BJ, Green TJ, Moser R, et al. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 2003; 77(3): 658–62

    PubMed  CAS  Google Scholar 

  36. Lamers Y. (6S)-5-methyltetrahydrofolate compared to folic acid supple-mentation: effect on risk markers of neural tube defects [dissertation; in German]. Bonn: University of Bonn, 2005

    Google Scholar 

  37. Lamers Y, Kehlenbach U, Prinz-Langenohl R, et al. [6S]-5-methyltetrahydro-folate as adequate alternative to folic acid supplementation [abstract]. 1st International Conference on Folates \3- Analysis, Bioavailability and Health (EuroFoodFolate 2004); 2004 Feb 11-14; Warsaw

    Google Scholar 

  38. Bostom AG, Shemin D, Bagley P, et al. Controlled comparison of L-5-methyltetrahydrofolate versus folic acid for the treatment of hyperhomo-cysteinemia in hemodialysis patients. Circulation 2000; 101(24): 2829–32

    Article  PubMed  CAS  Google Scholar 

  39. Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu Rev Nutr 1985; 5: 115–41

    Article  PubMed  CAS  Google Scholar 

  40. Pietrzik K, Golly I, Loew D. Handbuch Vitamine - fur Prophylaxe, Therapie und Beratung. Munich: Urban und Fischer Verlag, 2008

    Google Scholar 

  41. Institute of Medicine. Dietary reference intakes (DRI) for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington DC: National Academy Press, 1998 [online]. Available from URL: http://books.nap.edu/openbook.php?record_id=6015 [Accessed 2010 May 18]

  42. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr 2003 Jun; 77(6): 1474–7

    PubMed  CAS  Google Scholar 

  43. Ray JG, Vermeulen MJ, Langman LJ, et al. Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification. Clin Biochem 2003 Jul; 36(5): 387–91

    Article  PubMed  CAS  Google Scholar 

  44. Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post folic acid fortification period than in the pre folic acid fortification period. Am J Clin Nutr 2007 Oct; 86(4): 1187–92

    PubMed  CAS  Google Scholar 

  45. Metz J, Kelly A, Swett VC, et al. Deranged DNA synthesis by bone marrow from vitamin B12-deficient humans. Br J Haematol 1968; 14(6): 575–92

    Article  PubMed  CAS  Google Scholar 

  46. Ganeshaguru K, Hoffbrand AV. The effect of deoxyuridine, vitamin B12, folate and alcohol on the uptake of thymidine and on the deoxynucleoside triphosphate concentrationsin normal and megaloblastic cells. Br J Haematol 1978; 40(1): 29–41

    Article  PubMed  CAS  Google Scholar 

  47. Zittoun J, Marquet J, Zittoun R. Effect of folate and cobalamin compounds on the deoxyuridine suppression test in vitamin B12 and folate deficiency. Blood 1978; 51(1): 119–28

    PubMed  CAS  Google Scholar 

  48. Das KC, Herbert V. In vitro DNA synthesis by megaloblastic bone marrow: effect of folates and cobalamins on thymidine incorporation and de novo thymidylate synthesis. Am J Hematol 1989; 31(1): 11–20

    Article  PubMed  CAS  Google Scholar 

  49. Hoffbrand AV, Jackson BF. Correction of the DNA synthesis defect invitamin B12 deficiency by tetrahydrofolate: evidence in favour of the methyl-folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency. Br J Haematol 1993; 83(4): 643–7

    Article  PubMed  CAS  Google Scholar 

  50. Gutstein S, Bernstein LH, Levy L, et al. Failure of response to N5-methyl-tetrahydrofolate in combined folate and B12 deficiency: evidence in support of the ‘folate trap‐ hypothesis. Dig Dis 1973; 18(2): 142–6

    Article  CAS  Google Scholar 

  51. Smulders YM, Smith DE, Kok RM, et al. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methyl-folate trap. Br J Haematol 2006; 132(5): 623–9

    Article  PubMed  CAS  Google Scholar 

  52. Scott J. Methyltetrahydrofolate: the superior alternative to folic acid. In: Kramer K, Hoppel PP, editors. Nutraceuticals in health and disease prevention. New York: Marcel Dekker, 2001: 75–90

    Google Scholar 

  53. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111–3

    Article  PubMed  CAS  Google Scholar 

  54. Bailey LB, Moyers S, Gregory III JF. Folate. In: Bowman BA, Russell RM, editors. Present knowledge in nutrition. 8th ed. Washington, DC: ILSI Press, 2001: 214–29

    Google Scholar 

  55. Ueland PM, Rozen R. MTHFR polymorphisms and disease. Austin (TX): Landes Bioscience, 2005

    Google Scholar 

  56. Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic study on the utili-zation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol 2004; 141(5): 825–30

    Article  PubMed  CAS  Google Scholar 

  57. Litynski P, Loehrer F, Linder L, et al. Effect of low dose of 5-methyltetrahy-drofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C-T polymorphism of methylenetetrahydrofolate reductase. Eur J Clin Invest 2002; 32: 662–8

    Article  PubMed  CAS  Google Scholar 

  58. Pincus T, Yazici Y, Sokka T, et al. Methothrexate as the ‘anchor drug’ for the treatmentofearly rheumatoid arthritis. Clin Exp Rheumatol 2003; 21: S179–85

    PubMed  CAS  Google Scholar 

  59. Wong JM, Esdaile JM. Methotrexate in systemic lupus erythematosus. Lupus 2005; 14: 101–5

    Article  PubMed  CAS  Google Scholar 

  60. Warren RB, Griffiths CE. Systemic therapies for psoriasis: methotrexate, re-tinoids, and cyclosporine. Clin Dermatol 2008; 26: 438–47

    Article  PubMed  Google Scholar 

  61. Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009; 68: 1086–93

    Article  PubMed  CAS  Google Scholar 

  62. Katchamart W, Ortiz A, Shea B, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (an update systematic review and metaanalysis). J Rheumatol 2008; 58(6): 1197–8

    Google Scholar 

  63. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydro-folate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci U S A 2009; 106: 15424–9

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

All authors are members of the Folates in Gynecology Expert Group at Bayer Schering Pharma AG Germany. The scientific content of this contribution reflects the opinion of the authors, who were solely responsible for writing the paper. No organization had any role in the design, conduct of the review, collection, management, analysis, interpretation of data, preparation, review, or approval of the manuscript.

The authors would like to thank Bayer Schering Pharma AG Germany and Danielle Turner of Wolters Kluwer inScience Communications for providing journal formatting and submission support for the final draft of this manuscript.

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Authors and Affiliations

  1. Institute of Nutrition and Food Sciences, University of Bonn, Endenicher Allee 11–13, D-53115, Bonn, Germany

    Klaus Pietrzik

  2. Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida, USA

    Lynn Bailey

  3. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA

    Barry Shane

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  1. Klaus Pietrzik
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Correspondence to Klaus Pietrzik.

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Pietrzik, K., Bailey, L. & Shane, B. Folic Acid and L-5-Methyltetrahydrofolate. Clin Pharmacokinet 49, 535–548 (2010). https://doi.org/10.2165/11532990-000000000-00000

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