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Fasting plasma levels of unmetabolized folic acid in human subjects after chronic treatment with pharmacologic doses of folates

We have previously observed unmetabolized folic acid (FA) in plasma from fasting subjects who are not consumers of supplements or breakfast cereals. This was proposed to result from exposure to folic acid from U.S. grain fortification. Treatment of such subjects with 1.0 mg/d of folic acid for 10 weeks increased the average fasting plasma level of FA by several fold. In a new trial similar subjects were administered 2.5 mg/d or 5.0 mg/d of folic acid, 5.0 mg/d of 5‐methyl‐6S‐tetrahydrofolate (5‐MTHF), or placebo for 10 weeks. As in earlier studies, baseline plasma FA averaged 0.67 nM. Exposure to either dose of folic acid increased the fasting level by almost three‐fold, similar to that with 1.0 mg/d. Thus, the accumulation of FA appears to reach a maximum even at the lowest dose tested. Conceivably, this may also occur with the recommended daily intake (0.4 mg/d). Subjects given 5‐MTHF showed an increase of FA in plasma to 1.8 nM 90 min after the first dose. Ninety minutes after the last dose following 5 mg/d of the natural folate for 10 weeks, FA was only 1.3 nM. This indicates a decrease in the homeostatic level of folic acid bound to tissues by continuous displacement by 5‐MTHF. It is hypothesized that the site of retention of unmetabolized folic acid is the folate binding protein (the folate receptor) which is abundant in the kidney, choroid plexus and the placenta.