Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B₉).^[1] Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).^[2]

Comparison of available agents

• 
  Methotrexate
• 
  Pemetrexed
• 
  Raltitrexed
• 
  Pralatrexate

Mechanism

Many are primarily DHFR inhibitors, but raltitrexed is an inhibitor of thymidylate synthase, and pemetrexed inhibits both and a third enzyme.

Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle. Thus, they have a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well as causing the side-effects listed.

Limitations

Side-effects

The antifolate action specifically targets the fast-dividing cells, and tend to have adverse effects on the bone marrow, skin, and hair. As folate is vital in the first trimester of pregnancy for healthy fetal development, the use of antifolates is strongly contraindicated in pregnancy and carries significant teratogenic risk.

Low doses of methotrexate can deplete folate stores and cause side-effects that are similar to folate deficiency. Both high-folate diets and supplemental folic acid may help reduce the toxic side-effects of low-dose methotrexate without decreasing its effectiveness.^[8][9] Anyone taking low-dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.

Drugs that incidentally antagonize folate

The name antifolate usually refers to drugs whose folate antagonism is intentional. In contrast, there are some other drugs, of several drug classes, that antagonize folate incidentally, as an adverse effect, whether mildly or heavily. This effect is often not noticeable except when it causes a neural tube defect in a fetus carried by a woman taking the medication. Such drugs include some anticonvulsants (valproic acid, carbamazepine, phenobarbital, phenytoin, and primidone) and trimethoprim. Lamotrigine is also an anticonvulsant with known (from in vitro testing) weak anti-folate effects.^[12] Many of these, or metabolites thereof, seem to mimick the default aromatic ring moiety of folic acid (-N=C(NH₂)-NH-CO-C(R)=), especially lamotrigine and trimethoprim that share sequence (-N=C(NH₂)-N=C(NH₂)-C(R)=) with methotrexate, in which it is the primary modification to the folic acid structure.

See also

• Sulfonamides, a class of antimicrobials that work by inhibiting folate biosynthesis.

References

External links

• Antifolates at the U.S. National Library of Medicine Medical Subject Headings (MeSH)