What is the mechanism of action of leucovorin (folinic acid)?

Mechanism of Action of Leucovorin (Folinic Acid)

Leucovorin is a mixture of diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF), with the biologically active (-)-l-isomer functioning as a reduced folate that bypasses the dihydrofolate reductase enzyme to directly provide active folate metabolites for cellular processes. 1

Biochemical Mechanism

Leucovorin's mechanism of action is based on its unique properties as a reduced folate:

• Unlike folic acid, leucovorin does not require reduction by dihydrofolate reductase (DHFR) to participate in one-carbon transfer reactions 1
• After administration, l-leucovorin (l-5-formyltetrahydrofolate) is rapidly metabolized to:
  • 5,10-methenyltetrahydrofolate
  • Then to 5,10-methylenetetrahydrofolate
  • Finally to l,5-methyltetrahydrofolate 1

Clinical Applications Based on Mechanism

1. Rescue from Methotrexate Toxicity

• Methotrexate inhibits dihydrofolate reductase, preventing conversion of folate to its active forms
• Leucovorin bypasses this blockade by providing reduced folates directly, counteracting methotrexate's toxic effects 2, 1
• This "leucovorin rescue" is essential after high-dose methotrexate therapy to prevent severe toxicity

2. Enhancement of 5-Fluorouracil (5-FU) Activity

• Leucovorin enhances the therapeutic and toxic effects of 5-FU 1
• Mechanism:
  • 5-FU is metabolized to fluorodeoxyuridylic acid, which inhibits thymidylate synthase
  • Leucovorin is converted to 5,10-methylenetetrahydrofolate
  • This metabolite stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase
  • The result is enhanced inhibition of thymidylate synthase, a critical enzyme in DNA repair and replication 1

3. Treatment of Cerebral Folate Deficiency

• In conditions like cerebral folate deficiency (CFD), leucovorin can bypass the folate receptor alpha (FRα) by using the reduced folate carrier pathway 3
• This is particularly relevant in autism spectrum disorders where FRα autoantibodies may block normal folate transport into the brain 4, 3, 5

Pharmacokinetic Properties

• After administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates 1
• Oral absorption of leucovorin is saturable at doses above 25 mg:
  • At 25 mg dose: ~100% of l-isomer but only 20% of d-isomer is absorbed
  • Bioavailability: 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg 1
• After IV administration, serum total reduced folates reach peak levels rapidly (mean peak at 10 minutes) 1
• The terminal half-life for total reduced folates is approximately 6.2 hours 1

Clinical Implications of Mechanism

• Understanding leucovorin's mechanism explains why timing is critical in methotrexate rescue protocols
• The conversion to active metabolites explains why leucovorin enhances rather than antagonizes 5-FU activity
• The ability to bypass folate receptor alpha explains its utility in treating cerebral folate deficiency conditions

Common Pitfalls in Clinical Use

• Confusing leucovorin (folinic acid) with folic acid - they have different mechanisms and clinical applications
• Incorrect timing of leucovorin rescue after methotrexate can reduce chemotherapeutic efficacy if given too early
• Failure to adjust leucovorin dosing based on methotrexate levels can lead to inadequate rescue
• Not recognizing that leucovorin enhances rather than counteracts 5-FU toxicity

By understanding leucovorin's unique mechanism as a reduced folate that bypasses DHFR inhibition, clinicians can better utilize this agent in various therapeutic contexts from cancer treatment to management of folate metabolism disorders.