Metabolism of Folic Acid in Man

Folate is present in food primarily in reduced polyglutamate form. In the process of absorption, folate must be deconjugated. A significant precentage of folate is converted to the main transport and storage form (methylfolate) in the process of absorption. Adequate assessment of ability of a given agent to interfere with human folate metabolism requires evaluation of possible interference not only with intracellular use of folate but also ability to interfere with absorption of folate from food, bile folate excretion and reabsorption, and folate transport, distribution, cellular uptake, and release from cells. Evidence to date indicates that trimethoprim (TMP) reduces use of folate by normal human cells by the same mechanism as its action against invading organisms, i.e., by blocking dihydrofolate reductase. The therapeutic index of the drug (i.e., toxicity to invading organisms/toxicity to host cells) may be relatively narrow when the host cells are deficient in folate, resulting in megaloblastosis, anemia, leukopenia, and thrombocytopenia. Evidence so far suggests that the sulfamethoxazole (SMZ) part of TMP-SMZ therapy does not substantially damage folate metabolism in the host, although it may have occasional toxic effects, not currently known to be related to folate metabolism, on various organ systems.