What is leucovorin used for?

Uses of Leucovorin in Clinical Practice

Leucovorin is primarily used as a rescue agent to counteract the toxic effects of methotrexate and as a biochemical modulator to enhance the therapeutic effects of fluoropyrimidines like 5-fluorouracil in cancer treatment. 1

Primary Clinical Applications

1. Methotrexate Toxicity Rescue

• Mechanism of Action: Leucovorin (folinic acid) bypasses the dihydrofolate reductase enzyme inhibited by methotrexate, providing reduced folates necessary for DNA synthesis in normal cells 1
• Dosing Protocol for High-Dose MTX Toxicity:
  • Initial dose: Up to 100 mg/m² intravenously if methotrexate levels are unknown 2
  • Continue dosing every 6 hours until methotrexate levels are <0.05 μmol/L 2
  • For severe low-dose methotrexate toxicity, 15-25 mg IV every 6 hours is effective 3

2. Enhancing 5-Fluorouracil Efficacy in Cancer Treatment

• Mechanism: Leucovorin is converted to 5,10-methylenetetrahydrofolate, which stabilizes the binding of fluorodeoxyridylic acid to thymidylate synthase, enhancing 5-FU's inhibitory effect 1
• Common Regimens:
  • FOLFOX: Leucovorin 400 mg/m² IV over 2 hours on day 1 with oxaliplatin and 5-FU 4
  • FOLFIRI: Leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 4
  • Simplified biweekly infusional 5-FU/leucovorin (sLV5FU2): Leucovorin 400 mg/m² IV over 2 hours on day 1, followed by 5-FU bolus and continuous infusion 4

3. Prevention of Methotrexate-Induced Toxicity

• Used prophylactically in patients receiving methotrexate for conditions like rheumatoid arthritis
• Typically administered 24 hours after methotrexate dose to prevent bone marrow suppression while preserving therapeutic effect 5

4. Prevention of Pralatrexate-Induced Mucositis

• Oral leucovorin 25 mg 3 times daily for 2 consecutive days (total of 6 doses), starting 24 hours after each dose of pralatrexate 4

Clinical Pearls and Caveats

• Selective Protection: Leucovorin at low doses can selectively rescue normal cells while maintaining cytotoxic effects on tumor cells that have impaired folate transport mechanisms 6, 7
• Timing is Critical: For methotrexate rescue, leucovorin should be administered as soon as possible, ideally within the first 24 hours of toxicity 2
• Monitoring: During methotrexate rescue, monitor:
  • Complete blood counts daily
  • Renal function every 24 hours
  • Serum methotrexate levels (if available)
  • Urinary pH (maintain at ≥7.5) 2
• Leucovorin vs. Levo-leucovorin: Leucovorin 400 mg/m² is equivalent to levo-leucovorin 200 mg/m² 4

Common Pitfalls to Avoid

1. Underdosing in MTX toxicity: Insufficient leucovorin dosing can lead to persistent toxicity; dose should be calculated based on MTX levels and patient weight 6
2. Delayed administration: Effectiveness decreases significantly if administration is delayed beyond 24-48 hours after methotrexate exposure 2
3. Premature discontinuation: Monitoring should continue as pancytopenia can develop up to 6 weeks after methotrexate exposure 2
4. Medication interactions: Certain drugs (aspirin, phenytoin, sulfonamides, tetracycline) can displace methotrexate from albumin, increasing toxicity 4

Leucovorin represents a critical component in cancer treatment protocols and management of methotrexate toxicity, with its dual role as both a rescue agent and biochemical modulator making it an essential medication in clinical practice.