LV is a 5-formyl derivative of tetrahydrofolate (THF) that enters the cell via a reduced folate carrier (RFC) and is converted intracellularly to Me-THF independent of dihydrofolate reductase (DHFR). By bypassing the MTX’s primary mechanism of DHFR inhibition, LV acts as a “rescue” agent for cells exposed to high doses of MTX. As with MTX, low doses of LV are readily bioavailable, but doses >25 mg saturate intestinal absorption and require IV administration to ensure adequate drug exposure.

Administration of leucovorin after high-dose MTX administration is absolutely required to prevent fatal MTX toxicities. Leucovorin is typically administered 12 to 24 hours after MTX administration to allow for maximal cytotoxic anticancer activity before DHFR “rescue” of normal cells. The dose of leucovorin must be titrated based on MTX levels to ensure appropriate toxicity rescue and will be continued until MTX levels in the blood have been reduced to safer levels.