Leucovorin (Folinic Acid): Clinical Overview
Leucovorin (folinic acid) is a reduced folate derivative that serves as an antidote to folic acid antagonists like methotrexate and enhances the therapeutic effects of fluoropyrimidines such as 5-fluorouracil in cancer therapy. 1
Pharmacology and Mechanism of Action
Leucovorin is a mixture of diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF), with the biologically active component being the (-)-l-isomer, also known as Citrovorum factor or (-)-folinic acid. Unlike folic acid, leucovorin does not require reduction by the enzyme dihydrofolate reductase to participate in one-carbon transfer reactions 1.
After administration, leucovorin is rapidly metabolized to l-5-methyltetrahydrofolate, which becomes the predominant circulating form of the drug. Key pharmacokinetic properties include:
- After IV administration: Peak serum levels reach approximately 1,259 ng/mL within 10 minutes
- Terminal half-life: 6.2 hours for total reduced folates
- Metabolic pathway: Conversion via 5,10-methenyltetrahydrofolate to 5,10-methylenetetrahydrofolate, then to l,5-methyltetrahydrofolate 1
Clinical Applications
Leucovorin has two primary clinical applications:
1. Rescue therapy for methotrexate toxicity
Leucovorin counteracts the therapeutic and toxic effects of methotrexate by:
- Bypassing the inhibited dihydrofolate reductase enzyme
- Providing reduced folates necessary for cellular metabolism
- Preventing potentially life-threatening toxicity from high-dose methotrexate 2, 3
For methotrexate toxicity, leucovorin rescue should be initiated as soon as possible (within 24 hours) with dosing based on methotrexate levels, continuing until methotrexate levels are <0.05 μmol/L 3.
2. Enhancement of fluoropyrimidine efficacy
When used with 5-fluorouracil (5-FU), leucovorin:
- Enhances the therapeutic and toxic effects of 5-FU
- Stabilizes the binding of fluorodeoxyridylic acid to thymidylate synthase
- Increases inhibition of DNA synthesis in cancer cells 1
This biochemical modulation is utilized in several standard chemotherapy regimens for colorectal and gastric cancers, including:
- FOLFOX: Leucovorin + 5-FU + oxaliplatin
- FOLFIRI: Leucovorin + 5-FU + irinotecan 2
Dosing Considerations
Dosing varies by indication:
- For methotrexate rescue: Dosing is based on methotrexate levels, typically starting at 10-100 mg/m² and continuing until methotrexate levels are <0.05 μmol/L 3, 4
- For chemotherapy regimens: Standard doses range from 20-500 mg/m² depending on the specific protocol 2
- For systemic toxicity prevention: When administering intrathecal methotrexate, oral leucovorin 10 mg twice daily for 3 days may be given to mitigate systemic toxicity 2
Important Clinical Considerations
- Leucovorin does not appear to cross the blood-brain barrier in amounts sufficient to interfere with the effect of methotrexate in the CSF 2
- The l-isomer is the biologically active form; the d-isomer has minimal activity and may accumulate in plasma 5
- High-dose leucovorin can be used as sole therapy for methotrexate toxicity without the need for extracorporeal removal in many cases 6
- For severe low-dose methotrexate toxicity, studies have shown no significant difference in outcomes between 15 mg and 25 mg dosing every 6 hours 4
Formulations and Administration
Leucovorin calcium is available for intramuscular (IM) or intravenous (IV) administration, typically supplied in vials containing 10 mg/mL when reconstituted. It contains 0.002 mmol of calcium per mg of leucovorin 1.
When used in chemotherapy regimens, leucovorin 400 mg/m² is equivalent to levo-leucovorin 200 mg/m² 2.
By understanding the pharmacology and clinical applications of leucovorin, clinicians can effectively use this agent both as a rescue medication for methotrexate toxicity and as a biochemical modulator to enhance the efficacy of fluoropyrimidine-based chemotherapy regimens.