[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase

Br J Pharmacol. 2009 Dec;158(8):2014-21. doi: 10.1111/j.1476-5381.2009.00492.x.


Background and purpose: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C-->T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C-->T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives.

Experimental approach: Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (C(max)) and time-to-reach-maximum (t(max)) were calculated.

Key results: AUC and C(max) were significantly higher, and t(max) significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for t(max) after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF.

Conclusions and implications: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C-->T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Folic Acid / pharmacokinetics*
  • Genotype
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism*
  • Mutation
  • Polymorphism, Genetic*
  • Tetrahydrofolates / pharmacokinetics*
  • Vitamin B Complex / pharmacokinetics


  • Tetrahydrofolates
  • Vitamin B Complex
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-methyltetrahydrofolate