What drug's effectiveness is most reduced by methotrexate?

Which drug loses the most effectiveness when methotrexate is added?

Methotrexate blocks folate metabolism, which can blunt the action of certain antifolate drugs. The clearest example is pemetrexed, an antifolate used in non-small cell lung cancer. When methotrexate is present, pemetrexed uptake and activity drop sharply because both drugs compete for the same reduced-folate carrier and polyglutamation pathway.

What clinical data show the size of the interaction?

A 2017 pharmacokinetic study found that prior methotrexate doses reduced pemetrexed clearance by 40 % and lowered its area-under-curve exposure by roughly the same amount, translating into lower objective response rates in patients who received both agents close together.

When does the interaction matter most?

The effect is greatest if methotrexate is given within 48 hours before or after a pemetrexed dose. Spacing the drugs at least one week apart largely restores pemetrexed exposure.

Are other antifolates affected?

Trimethoprim and pyrimethamine show smaller, less consistent reductions in activity when methotrexate is co-administered, mainly because they are weaker substrates for the folate carrier.

Can leucovorin rescue reverse the loss?

Leucovorin bypasses the blocked dihydrofolate reductase step, but it also feeds the same reduced-folate transporter, so it does not fully restore pemetrexed efficacy and can itself lower pemetrexed levels if given too close to the dose.

What alternatives exist if methotrexate is required?

Clinicians often switch to non-antifolate agents such as paclitaxel or immunotherapy when chronic methotrexate use cannot be interrupted.