Which combination is most likely to cause deterioration due to antifolate interaction?

Which combination is most likely to cause deterioration due to antifolate interaction?

• A. Methotrexate + Paracetamol
• B. Methotrexate + Trimethoprim
• C. Methotrexate + Metformin
• D. Methotrexate + Amoxicillin

Answer: (B)

Antifolate interactions happen when two drugs block the folate pathway, shrinking the pool of active folate needed for DNA synthesis in rapidly dividing cells. Methotrexate inhibits dihydrofolate reductase, a key step in making tetrahydrofolate. Trimethoprim can also inhibit dihydrofolate reductase, and at clinically relevant doses it can affect human DHFR as well. When these two are combined, their effects add up or even become synergistic, significantly increasing toxicity—most notably bone marrow suppression (pancytopenia) and mucosal damage. That’s why methotrexate plus trimethoprim is the combination most likely to cause deterioration due to an antifolate interaction. Other options don’t involve this direct, overlapping antifolate mechanism, so their interactions don’t carry the same level of risk from folate pathway inhibition.

Antifolate interactions happen when two drugs block the folate pathway, shrinking the pool of active folate needed for DNA synthesis in rapidly dividing cells. Methotrexate inhibits dihydrofolate reductase, a key step in making tetrahydrofolate. Trimethoprim can also inhibit dihydrofolate reductase, and at clinically relevant doses it can affect human DHFR as well. When these two are combined, their effects add up or even become synergistic, significantly increasing toxicity—most notably bone marrow suppression (pancytopenia) and mucosal damage. That’s why methotrexate plus trimethoprim is the combination most likely to cause deterioration due to an antifolate interaction.

Other options don’t involve this direct, overlapping antifolate mechanism, so their interactions don’t carry the same level of risk from folate pathway inhibition.