Polyglutamate forms

The higher RDA is specified to allow for absorption of only 25% of folic acid activity in a manner comparable to the crystalline folic acid and to allow for a wide range of availability of the polyglutamate form (13). 

Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N 5-methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa. 

When the contents of peak 2 were boiled at pH 8.0 and applied to a second column of Sephadex 6-25 the profile observed in Figure 3A was obtained whose peaks corresponded to known standards for free MTX and polyglutamate forms of MTX. Similar results were obtained when an aliquot of combined fractions 55 to 77 were applied to the Sephadex 6-25 column (Figure 3B). 

On the surface, it would appear that a drug which could not form polyglutamates and therefore not be well retained by cells would be an inappropriate candidate for an antitumor drug. However, in common with all cancer chemotherapeutic agents, the dose-limiting toxicity of MTX is associated with non-tumor tissue (e.g., liver, marrow, etc.) and the highly retentive polyglutamate forms... 

Stereochemical Differences in FMTX Action. As noted above, cell culture studies on the non-radioactive erythro,threo mixture suggested that the fluorinated analog is not converted to polyglutamate forms (6). That conclusion has been... 

The hver, which stores half of the body s folate, takes up much of the folate from the portal circulation uptake may be through active transport or receptor-mediated endocy-tosis. Within the liver, FH4 is reconjugated to the polyglutamate form before being used in reactions. A small amount of the folate is partially degraded, and the components enter the urine. A relatively large portion of the folate enters the bile and is subsequently reabsorbed (very similar to the fate of bile salts in the enterohepatic circulation). 

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