What is the difference between folic acid and folinic acid (leucovorin)?

Differences Between Folic Acid and Folinic Acid (Leucovorin)

Folic acid and folinic acid (leucovorin) are different forms of folate with distinct biochemical properties, metabolic pathways, and clinical applications.

Biochemical Differences

• Folic acid is a synthetic form of folate that requires enzymatic conversion to become biologically active. It must undergo reduction to dihydrofolate and then to tetrahydrofolate before it can function as a cofactor 1, 2.

• Folinic acid (leucovorin) is a naturally occurring reduced folate (N5-formyltetrahydrofolic acid) that is already in an active form and can directly enter cellular metabolism without requiring the reduction steps needed by folic acid 1, 3.

Metabolic Pathway Differences

• Folic acid requires conversion by dihydrofolate reductase in the liver to become metabolically active, requiring multiple enzymatic steps to reach the active tetrahydrofolate form 2.

• Folinic acid bypasses the dihydrofolate reductase step and is readily converted to other active folate metabolites, particularly 5-methyltetrahydrofolate (5-MTHF), which is the predominant circulating form of folate 3, 4.

Absorption and Bioavailability

• Folic acid is absorbed rapidly from the small intestine, primarily from the proximal portion. After oral administration, it appears in plasma within 15-30 minutes, with peak levels generally reached within 1 hour 2.

• Folinic acid when administered orally is rapidly converted to 5-methyltetrahydrofolate. Studies show that after oral administration of leucovorin, almost all the folate in serum and urine is in the form of 5-methyltetrahydrofolate, with peak serum levels observed around 3 hours after administration 4.

Clinical Applications

Folic Acid Applications:

• Neural tube defect prevention: 0.4 mg daily for women of childbearing age; 4 mg daily for women with previous NTD-affected pregnancy 1, 5
• Treatment of folate deficiency: 1-5 mg daily 5
• Prevention of folate deficiency in patients on medications that interfere with folate metabolism (e.g., methotrexate, sulphasalazine) 1

Folinic Acid Applications:

• Rescue therapy after high-dose methotrexate to prevent toxicity 6
• More efficient at restoring body folate stores in patients with inflammatory bowel disease treated with sulphasalazine compared to folic acid 1, 7
• Treatment of certain metabolic disorders where folic acid metabolism is impaired

Key Practical Differences

1. Metabolic activation: Folinic acid doesn't require the enzyme dihydrofolate reductase for activation, making it useful in situations where this enzyme is inhibited (e.g., methotrexate therapy) 8.

2. Efficacy in drug interactions: Folinic acid is more effective when used with medications that inhibit folate metabolism. An Italian study showed folinic acid was more efficient than folic acid in restoring body stores of folate in IBD patients treated with sulphasalazine 1, 7.

3. Bypass of genetic polymorphisms: Folinic acid can bypass genetic polymorphisms affecting folate metabolism, potentially making it more effective in individuals with these variants 5, 9.

Clinical Decision-Making Algorithm

1. For general supplementation and prevention:

   • Use folic acid 0.4 mg daily for most individuals
   • Use folic acid 0.4-1 mg daily for pregnant women
   • Use folic acid 4 mg daily for women with previous NTD-affected pregnancy

2. For patients on medications affecting folate metabolism:

   • For methotrexate: Use folic acid 5 mg once weekly 24-72 hours after methotrexate, or 1 mg daily for 5 days per week
   • For sulphasalazine: Consider folinic acid 15 mg daily for more efficient restoration of folate stores

3. For rescue therapy after high-dose methotrexate:

   • Use folinic acid (leucovorin) as it bypasses the inhibited dihydrofolate reductase enzyme

Potential Pitfalls

• High doses of either form (>1 mg/day) may mask vitamin B12 deficiency by correcting the hematological abnormalities while allowing neurological damage to progress 5.

• When treating folate deficiency, always evaluate for concurrent B12 deficiency to avoid missing this important diagnosis 5.

• Folic acid may interact with certain anticonvulsants and reduce their effectiveness, whereas folinic acid might have fewer interactions 9.

• Folinic acid is generally more expensive than folic acid, which may impact treatment decisions when cost is a consideration.