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Despite efforts to increase folic acid (FA) intake, even within countries mandating FA fortification, there remain pregnant women with folate levels inadequate to minimize congenital disorders (e.g., of the neural tube, heart, and lip/palate). The pharmacokinetics of FA and [6S]-5-methyltetrahydrofolate (5-MTHF) were examined to find a reliable and minimal dose for rapidly rescuing folate status prior to critical periods of embryonic development. Serum total folate increased much more rapidly over the first four days in insufficient women given 7.5 mg doses of 5-MTHF than the same regimen of FA (P for trend <0.0001). Nearly all women given 7.5 mg 5-MTHF (every 12 hours, five doses total) almost immediately reached 50 nM serum total folate. Moreover, this level could be maintained by subsequent administration of 0.4 mg/d of folic acid. Thus, 5-MTHF enables repletion of folate stores more quickly and uniformly than FA and without exposure to unmetabolized FA.

Objective: To investigate the effect of simultaneous administration of [6S]-5-methyltetrahydrofolic acid ([6S]-5-CH(3)H(4)PteGlu) with L-ascorbic acid (L-AA) on serum folate concentrations in healthy male subjects., Subjects and Methods: A total of nine healthy male volunteers were recruited. Serum folate concentrations were measured before and up to 8 h after administration of each treatment (1) placebo, (2) 343 microg [6S]-5-CH(3)H(4)PteGlu), (3) 343 microg [6S]-5-CH(3)H(4)PteGlu) with 289.4 mg L-AA and (4) 343 microg [6S]-5-CH(3)H(4)PteGlu) with 973.8 mg L-AA (n=10 samples per treatment)., Results: Serum folate concentrations significantly increased compared with baseline values, starting from 30 min after [6S]-5-CH(3)H(4)PteGlu administration and remained significantly higher than baseline values during the first 6 h for treatments 3 and 4, and during the first 4 h for treatment 2. Maximal serum folate responses were observed between 0.5 and 1.5 h after [6S]-5-CH(3)H(4)PteGlu consumption and significantly differed between treatments 2 and 4 (P<0.05). When [6S]-5-CH(3)H(4)PteGlu was concurrently administered with 289.4 or 973.8 mg L-AA, the total serum folate response, calculated as the area under the curve (AUC), was significantly improved (46.5+/-4.0 and 53.0+/-4.0 vs 34.3+/-3.8 h nmol/l, P<0.05). No significant difference in AUC was found between the 289.4 and the 973.8 mg L-AA treatments., Conclusions: Administration of a physiological dose of [6S]-5-CH(3)H(4)PteGlu with L-AA significantly improved the measured serum folate response in folate saturated healthy men.

Objectives: To assess the effects of supplementation with the diastereoisomer of 5-methyltetrahydrofolate ([6S]5-methylTHF), as an alternative supplement for folic acid, on folate absorption and elimination, in two age groups., Design: A randomized, double-blind intervention study., Subjects: A total of 12 young (<30 y) and 12 middle-aged (> or =50 y) healthy volunteers were recruited., Methods: Volunteers were randomized to receive daily supplementation with 400 mug folic acid or equimolar amounts of [6S]5-methylTHF during 5 weeks. Before and after supplementation, absorption and initial elimination were calculated following oral [(2)H(2)]folic acid test doses using isotope kinetics in plasma., Results: Folic acid absorption was lower in the middle-aged as compared to the young adults, both before (P = 0.03) and after (P = 0.05) supplementation. In the young adults, absorption decreased by 22% after [6S]5-methylTHF and increased by 21% after folic acid (P = 0.02). In the other age group, no such changes were found. The folate rate constant of elimination increased after folic acid supplementation in the young (+50%; P = 0.05) but not in the middle-aged (+18%; P = 0.5) adults., Conclusions: Young adults show increased folate turnover after folic acid supplementation relative to the effect of [6S]5-methylTHF supplementation. Similar differences are not observed in middle-aged adults, in whom folic acid absorption was found to be lower as compared to the young adults., Sponsorship: Financial support was received from the European Union 5th Framework Programme (Grant QLRT-1999-00576).

Previously reported work from this laboratory has shown that, in man, the formation of plasma 5-methyltetrahydrofolic acid (5MeTHF) from orally administered pteroylmonoglutamic acid (PGA) obeys Michaelis-Menten kinetics. The regression equation obtained from a plot of the reciprocal amount of 5MeTHF formed (micrograms per litre plasma/min) as a function of reciprocal amount of PGA administered (micrograms/kg body weight) provides a useful means of calculating the improved efficiency of 5MeTHF formation by dividing the total dose of PGA into smaller doses.