Leucovorin

Class: Reduced folate (vitamin B9) analog

Mechanism of Action

• Bypasses dihydrofolate reductase (DHFR) → replenishes reduced folate pools
• Enhances or counteracts the effects of antifolate drugs depending on context:
  • Rescue after high-dose methotrexate → protects normal cells
  • Enhances 5-FU activity by stabilizing the 5-FU–thymidylate synthase complex

Indications

1. Methotrexate rescue (high-dose MTX regimens in ALL, osteosarcoma, lymphoma)
2. Enhancer of 5-FU cytotoxicity (e.g., colorectal cancer regimens)
3. Antidote for folate antagonist toxicity (e.g., accidental methotrexate overdose, trimethoprim toxicity)

Dosing

• MTX rescue:
  • Typically begins 24 hours after methotrexate infusion
  • Dose and duration guided by MTX levels (e.g., 10–15 mg/m² every 6 hours, or higher)
• 5-FU enhancement:
  • 200–400 mg/m² IV bolus before or with 5-FU
• Available as IV, IM, or oral (IV preferred for high-dose rescue)

Key Adverse Effects

• Generally well tolerated
• Rare: allergic reactions, rash, GI upset
• Can mask vitamin B12 deficiency (with long-term use)

Monitoring

• Serum methotrexate levels and renal function (in high-dose MTX regimens)
• CBC and electrolytes if used with chemotherapy
• Assess for timely initiation (delays can worsen toxicity)

Drug Interactions

• Avoid concurrent use with oral calcium folinate and methotrexate (interferes with MTX effect)
• Enhances efficacy and toxicity of 5-FU

Other Notes

• Not interchangeable with folic acid or levoleucovorin (isomer-specific dosing may differ)
• Oral absorption saturates at higher doses → IV preferred for MTX rescue
• Must be continued until MTX levels fall below safe threshold (<0.05–0.1 μM depending on protocol)