Food folates (polyglutamate derivatives) are hydrolyzed to monoglutamate forms in the gut before absorption across the intestinal mucosa. This cleavage is accomplished by a γ-glutamylhydrolase, more commonly called folate conjugase. The monoglutamate form of folate is actively transported across the proximal small intestine by a saturable pH-dependent process. When pharmacological doses of the monoglutamate form of folate are consumed, it is also absorbed by a nonsaturable mechanism involving passive diffusion.

Monoglutamates, mainly 5-methyl-tetrahydrofolate, are present in the portal circulation. Much of this folate can be taken up by the liver, where it is metabolized to polyglutamate derivatives and retained or released into the blood or bile. Approximately two-thirds of the folate in plasma is protein bound. A variable proportion of plasma folate is bound to low-affinity protein binders, primarily albumin, which accounts for about 50 percent of bound folate. Low levels of high-affinity folate binders are also present in plasma.

Cellular transport of folate is mediated by a number of different folate transport systems, which can be characterized as either membrane carriers or folate-binding protein-mediated systems. These transport systems are not saturated by folate under physiological conditions, and folate influx into tissues would be expected after any elevation in plasma folate after supplementation.

Folate concentrations in liver of 4.5 to 10 µg/g were reported after liver biopsies (Whitehead, 1973). Because the adult male liver weighs approximately 1,400 g, the total quantity of folate in the liver would be approximately 6 to 14 mg. If the liver is assumed to contain 50 percent of the body stores of folate, the estimated total body folate store would be 12 to 28 mg. Using the same assumption, Hoppner and Lampi (1980) determined average liver folate concentrations to be approximately 8 µg/g (range 3.6 to 14.8 µg/g) after autopsy; the liver folate content would be approximately 11 mg and total body folate 22 mg.

Before being stored in tissue or used as a coenzyme, folate monoglutamate is converted to the polyglutamate form by the enzyme folylpolyglutamate synthetase. When released from tissues into circulation, folate polyglutamates are reconverted to the mono-