Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts

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.

Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy

“…While folic acid has been used in prenatal supplements, the use of folinic acid or MTHF may be worth considering. Pharmacokinetic studies in humans have shown that MTHF is absorbed and retained better than folic acid [50]. Our rat studies also show that MTHF and both forms of folinic acid have comparable absorption.…”

Conversion of calcium‐l‐methylfolate and (6S)‐5‐methyltetrahydrofolic acid glucosamine salt into dietary folate equivalents

“…For three acute randomised cross‐over studies, the AUC (PTF or ( 6S )‐5‐MTHF) was calculated. Their RoB was assessed by the panel to be low (Pentieva et al., 2004), intermediate (for AUC for ( 6S )‐5‐MTHF) (Obeid et al., 2020) or high (Prinz‐Langenohl et al., 2009; Obeid et al., 2020). Single doses of 5‐MTHF tested were 416 μg (Prinz‐Langenohl et al., 2009), 436 μg (Obeid et al., 2020) and 500 μg (Pentieva et al., 2004).…”

“…Their RoB was assessed by the panel to be low (Pentieva et al., 2004), intermediate (for AUC for ( 6S )‐5‐MTHF) (Obeid et al., 2020) or high (Prinz‐Langenohl et al., 2009; Obeid et al., 2020). Single doses of 5‐MTHF tested were 416 μg (Prinz‐Langenohl et al., 2009), 436 μg (Obeid et al., 2020) and 500 μg (Pentieva et al., 2004). In one study (Pentieva et al., 2004), the tested substances were given with a meal, while they were consumed on an empty stomach in the others (Prinz‐Langenohl et al., 2009; Obeid et al., 2020).…”

“…Most of the acute studies used CaLMF as a form of 5‐MTHF (Pentieva et al., 2004; Prinz‐Langenohl et al., 2009; Obeid et al., 2020), except for one study in which sodium 5‐MTHF (Obeid et al., 2020) was used and two that used the free form, i.e. 5‐MTHF acid (Tamura and Stokstad, 1973; Gregory et al., 1992).…”

Evaluation of Cardiovascular Toxicity of Folic Acid and 6S-5-Methyltetrahydrofolate-Calcium in Early Embryonic Development

“…Furthermore, we comparatively studied MTHF-Ca while analyzing FA. Unmetabolized FA in plasma has been found to occur regularly after supplementation with FA [ 46 ]. Our findings from the current study may raise concerns about excess FA supplementation.…”