Abstract
(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), Cmax, and Tmax of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC0–8 h of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and Cmax (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC0–8 h for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC0–8 h did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC0–8 h and Cmax of plasma (6S)-5-Methyl-THF compared to folic acid. The Na- and Ca- salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations.
Highlights
Folates, an essential class of B vitamins, donate one-carbon units during the de-novo synthesis of purines, formylmethionyl-tRNA, thymidylate, serine, and methionine
The present study investigated the pharmacokinetics of (6S)-5-Methyl-THF-Na compared to folic acid in adults
area under the curve (AUC) of plasma (6S)-5-Methyl-THF between (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca have shown that the calcium and monosodium salts are not likely to differ in their pharmacokinetics
Summary
An essential class of B vitamins, donate one-carbon units during the de-novo synthesis of purines, formylmethionyl-tRNA, thymidylate, serine, and methionine. Folates are needed for synthesis of nucleotides that constitute DNA and RNA structures. The neurotoxic amino acid homocysteine is converted to methionine using the methyl group of (6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF). The methyl group of folate is used to synthesize S-adenosylmethionine that is needed for many methyltransferases (i.e., DNA methyltransferase), explaining the wide effects of folate deficiency. Folate deficiency is associated with hyperhomocysteinemia, and several diseases such as anemia, depression, and pregnancy complications [2]. Supplementation of folate to women before and during early pregnancy lowers the risk of birth defects [3,4]
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