Folinic acid

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Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine.<ref name=BNF69>Template:Cite book</ref><ref name=AHFS2016>Template:Cite web</ref> It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency, anemia, and methanol poisoning.<ref name=AHFS2016/><ref>Template:Cite book</ref> It is taken by mouth, injection into a muscle, or injection into a vein.<ref name=AHFS2016/>

Side effects may include trouble sleeping, allergic reactions, or fever.<ref name=BNF69/><ref name=AHFS2016/> Use in pregnancy or breastfeeding is generally regarded as safe.<ref name=BNF69/> When used for anemia it is recommended that pernicious anemia as a cause be ruled out first.<ref name=AHFS2016/> Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.<ref name=AHFS2016/>

Folinic acid was first made in 1945.<ref>Template:Cite book</ref> In 2025, the United States Food and Drug Administration began approving leucovorin calcium tablets for cerebral folate deficiency, bypassing standard review and drawing expert criticism.<ref name=":0">Template:Cite web</ref><ref name="Jewett_2025" /> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref>

Medical uses

File:Levofolinic acid.svg

Levofolinic acid

Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).<ref>Template:Cite journal</ref>

To reduce effects of methotrexate

Folinic acid is administered after methotrexate as part of a comprehensive chemotherapy regimen to help prevent bone marrow suppression and inflammation of the gastrointestinal mucosa. However, no apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity.<ref>Therapeutic Information Resources Australia (2004). Calcium Folinate (Systemic) in AUSDI: Australian Drug Information for the Health Care Professional. Castle Hill: Therapeutic Information Resources Australia.Template:Page needed</ref>

While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be redosed until the methotrexate level is less than 5 x 10⁻⁸ M.<ref>Template:Cite web</ref>

Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in rheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.<ref>Template:Cite journal</ref>

Cerebral folate deficiency

Folinic acid is also used in the treatment of cerebral folate deficiency, a syndrome in which the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF.<ref name="Gordon2009">Template:Cite journal</ref>

The US Food and Drug Administration (FDA) began the process of approving leucovorin calcium tablets for treating cerebral folate deficiency.<ref name="FDA">Template:Cite web</ref>

Other uses or indications

Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.

Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine, although its value for this indication has not been clearly established.<ref>Template:Cite book</ref> It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.

In pyridoxine-dependent epilepsy, folinic acid may be used as additional therapy if pyridoxine or pyridoxal phosphate fails to fully control the seizures.<ref name="pmid35053812">Template:Cite journal</ref>

Side effects

Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.<ref name="Jardine-1996">Template:Cite journal</ref> Severe neurotoxicity due to intrathecal folinic acid as treatment for intrathecally-administered methotrexate was first noted in an 11-year-old boy being treated for acute lymphocytic leukemia.<ref name="Jardine-1996" />

In cancer patients, rare hypersensitivity reactions to folinic acid have been described.<ref name="pmid26042586">Template:Cite journal</ref>

Drug interactions

• Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe enterocolitis, diarrhea, and dehydration.Template:Citation needed
• Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients.<ref>Template:Cite journal</ref>

Mechanism of action

Template:More citations needed Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin activity equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy. In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists.

Although the mechanism is not very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells.<ref name="pmid2448654">Template:Cite journal</ref>

Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal DNA replication processes can proceed.

Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability.<ref>Template:Cite journal</ref> Levoleucovorin was approved by the FDA in 2008.<ref>Template:Cite web</ref>

History

Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann.<ref>Template:Cite journal</ref> This resulted in it being called "citrovorum factor", meaning citrovorum growth factor. It had an unknown structure, but was found to be a derivative of folate that had to be metabolized in the liver before it could support growth of L. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems resulted in increased citrovorum factor activity in the cell-free supernatants (producing, as now known, the 5-formyl derivative), and from this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.<ref>Rabinowitz, J. C., & Pricer Jr, W. E. (1956). Formimino-tetrahydrofolic acid and methenyltetrahydrofolic acid as intermediates in the formation of N10-formyltetrahydrofolic acid. Journal of the American Chemical Society, 78(21), 5702-5704.</ref>

On 22 September 2025, the US Food and Drug Administration (FDA) under medical contrarian and US secretary of health and human services Robert F. Kennedy Jr. initiated the process of approving leucovorin calcium tablets for the treatment of cerebral folate deficiency, a condition associated with developmental delays, autistic features, seizures, and movement issues, based on literature allegedly showing potential benefit, while noting further research is needed for broader neuropsychiatric populations.<ref name="FDA" /> The approval bypassed the FDA's standard rigorous drug-review procedures, drawing criticism from experts and leading to increased sales of over-the-counter folinic acid supplements.<ref name="Jewett_2025">Template:Cite news</ref><ref name="Stobbe_2024">Template:Cite web</ref>

Names

Template:Unreferenced section Folinic acid should be distinguished from folic acid (vitamin B₉). However, folinic acid is a vitamer for folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S-form of the molecule. They are the only forms of the molecule that are known to be biologically active.

It is generally administered as the calcium or sodium salt (calcium folinate [INN], sodium folinate, leucovorin calcium, leucovorin sodium).

External links

• Template:Cite web