Folic acid-displacement in man

Seven compounds, either closely related in structure to folic acid or fragments of the folic acid molecule, were tested in man for the ability to displace a dose of 5 μg of tritium-labeled folic acid/kg (20μc) administered 24 hr previously. The compounds were administered intravenously at a dosage of 1 μmole/kg, and their ability to displace intracellular folic acid was assessed by measurement of folic acid radioactivity appearing in the urine in the next 6 hr. Those compounds in which the structural integrity of the pteridine moiety of folic acid was unimpaired were effective folic acid-displacing agents; compounds lacking the pteridine moiety were unable to displace folic acid; compounds having a modified pteridine moiety showed only weak displacing ability, despite the very high affinity in vitro of one of them (metnotrexate) for the enzyme dihydrofolate reductase. The results suggest that in man, a structurally intact pteridine moiety is necessary for effective displacement of folic acid from cells. Folic acid-displacing ability cannot be explained solely on the basis of relative affinity for dihydrofolate reductase; it is postulated that an additional factor in folic acid-displacing ability is relative affinity for a folic acid transport mechanism.