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Nutritional Models

Differential Kinetic Behavior and Distribution for Pteroylglutamic Acid and Reduced Folates: a Revised Hypothesis of the Primary Site of PteGlu Metabolism in Humans¹

Nutrition Department, Institute of Food Research, Norwich NR4 7UA, United Kingdom; and ^* Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611-0370

²To whom correspondence should be addressed. E-mail: tony.wright{at}bbsrc.ac.uk.

Single ¹³C₆-labeled doses of pteroylmonoglutamic acid (PteGlu: 634 nmol; n = 14), (6S-)5-formyltetrahydrofolic acid (431–569 nmol; n = 16), or [¹⁵N_1–7]-intrinsically labeled spinach (mainly 5-methyltetrahydrofolate) (588 nmol; n = 14) were fed to fasting adult volunteers. Plasma-labeled 5-methyltetrahydrofolic acid responses were monitored for 8 h. There was a slower rate of increase in plasma-labeled 5-methyltetrahydrofolic acid and longer time to peak (171 ± 9 min; mean ± SEM) following an oral dose of [¹³C₆]PteGlu than either [¹³C₆]5-formyltetrahydrofolic acid (54 ± 10 min) or [¹⁵N_1–7]spinach folate (60 ± 13 min) suggesting saturated metabolic capacity for the biotransformation of PteGlu. Mathematical modeling generated a significantly higher mean "apparent absorption" for 5-formyltetrahydrofolic acid (38%) and spinach folate (44%) than for PteGlu (24%). The high "relative absorption" of reduced folates to PteGlu was unexpected given that PteGlu itself, from ¹⁴C-tracer mass balance experiments, is almost completely absorbed. Although it is ubiquitously accepted that a physiological dose of PteGlu is reduced and methylated in the epithelial cells of the small intestine, and that essentially only 5-methyltetrahydrofolic acid is exported into the hepatic portal vein (HPV), as is the case for absorbed reduced 1-carbon-substituted folates, modeling indicated greater liver sequestration when PteGlu was used as the test dose, suggesting that PteGlu enters the HPV unaltered and that the liver is the primary site of initial metabolism. Because of the observed differential plasma response and the hypothesized difference in the site of initial metabolism, the historical use of PteGlu as a "reference folate" in studies of folate bioavailability is seriously questioned.

KEY WORDS: • pteroylmonoglutamic acid • folate • absorption • isotopes • modeling

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