Methotrexate blocks nucleic acid synthesis by inhibiting folic acid activation via dihydrofolate reductase. Leucovorin, also known as folinic acid, is folic acid in its active (reduced) form, so it allows nucleic acid synthesis to proceed even in the presence of methotrexate. Although available in different formulations, intravenous is preferred in the setting of methotrexate toxicity and should be started promptly. Methotrexate becomes increasingly polyglutamated; the longer it stays in the cell, the polyglutamated methotrexate becomes less susceptible to reversal with leucovorin. Methotrexate and serum creatinine levels require at least daily monitoring; leucovorin should continue until the methotrexate level falls below 0.05 micromolar. Since the rate of methotrexate elimination is dependent on urine output, hydration and urinary alkalinization should also be optimized along with leucovorin therapy.
References: StatPearls Leucovorin