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A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses^1,2,3,4

¹ From the Wageningen Centre for Food Sciences, Wageningen, Netherlands (AM-B, PV, and MBK); the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands (AM-B, PV, CEW, MBK, and FJK); the State Institute for Quality Control of Agricultural Products, Wageningen, Netherlands (JAvR and JJPL); and the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Champaign, IL (RBvB and SDG)

Background: The bioavailability of dietary folate may be hampered by the need of the glutamate moieties to be deconjugated before absorption. Previous studies comparing the bioavailabilities of polyglutamyl and monoglutamyl folic acid had inconsistent results.

Objective: The objective was to estimate the bioavailability of polyglutamyl relative to that of monoglutamyl folic acid by using a sensitive stable-isotope approach that allowed for the administration of multiple low doses in humans.

Design: Twenty subjects aged 20–50 y ingested 2 capsules daily for 28 d; each capsule contained 50 nmol [¹³C₆]hexaglutamyl and 50 nmol [¹³C₁₁]monoglutamyl folic acid. Amounts of the isotopically labeled compounds in the capsules were verified by various methods. The degrees of isotopic enrichment of plasma 5-methyltetrahydrofolate with ¹³C₆ and ¹³C₁₁ were measured by using liquid chromatography tandem mass spectrometry, and the ratio of ¹³C₆ to ¹³C₁₁ (¹³C₆:¹³C₁₁) in plasma on day 28 was used as a measure of their relative bioavailability.

Results: The ¹³C₁₁:¹³C₆ in plasma 5-methyltetrahydrofolate reached equilibrium on day 4 and was 0.66 (95% CI: 0.58, 0.74) on day 28. The ¹³C₁₁:¹³C₆ content in the capsules varied between 1.18 and 1.96. After correction for this ratio, the estimated bioavailability of hexaglutamyl relative to that of monoglutamyl folic acid was 78%.

Conclusion: Multiple dosing of low amounts of labeled folic acid is a sensitive, accurate, and efficient method of measuring the relative bioavailability of folic acid compounds, provided that the administered doses can be reliably assessed.

Key Words: Folic acid • bioavailability • stable isotopes • humans • mass spectrometry

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