The Differences Between Folic Acid and Folinic Acid

Folic acid and folinic acid are folates belonging to the vitamin group B9. Their uses are different from a clinical point of view, as their mechanism of action and biochemical routes differ.

Written and verified by el biólogo Samuel Antonio Sánchez Amador.

Last update: 17 December, 2022

There are thousands of compounds used in the medical field to combat deficiencies, neoplasms, and other pathological processes. Due to the wide variety that exists, they’re sometimes presented under names that are so similar that they end up creating confusion. This is the case with folic acid and folinic acid.

Both folic acid and folinic acid are part of the vitamin B complex and are classified in the group of folates. Although their pharmacological action is relatively similar, each of these compounds shines in specific medical fields. Keep reading and learn everything you need to know about folic and folinic acid.

What is folic acid?

As indicated by the National Library of Medicine of the United States, folic acid is a type of water-soluble vitamin belonging to the vitamin B complex. It’s also called vitamin B9 or vitamin M and its main function is to help the body create new cells. Among other things, this compound is necessary for the maturation of structural proteins and hemoglobin.

Folic acid is the synthetic form of folate, a B vitamin found naturally in many foods. The body requires folate for the synthesis of DNA and other types of genetic material, which are vital in cell division and proliferation. Once in the body, folate is transformed into tetrahydrofolic acid and is used as a cofactor in various biological reactions.

Folate is stored in small concentrations naturally in the liver and kidneys. Therefore, chronic alcoholism (which destroys liver tissue) is one of the main causes of its deficiency. Digestive absorption disorders, hemolytic anemia, and particularly demanding pregnancies are also triggers.

What is folinic acid?

The National Cancer Institute (NCI) defines folinic acid as “A form of folic acid used alone or with other drugs to treat certain types of colorectal cancer and anemia and to lessen the toxic effects of the anticancer drug methotrexate or other substances that block the action of folic acid.” It’s a reduced form of vitamin B9 (specifically, a 5-formyl derivative of tetrahydrofolic acid) known in clinical practice as leucovorin.

Folinic acid can be easily converted to other reduced derivatives of folic acid. Therefore, it’s considered to be a vitamer of the B9 complex. As indicated in Medical Dictionary.net, this means that its vitamin activity is more or less interchangeable with that of folate and folic acid when used. Its main utility in clinical medicine is to counteract the toxicity of certain chemotherapeutic agents.

It’s important to note that folinic acid exists naturally in the human body. This compound represents approximately 90% of the functional derivatives of folate in blood plasma, which has made it a very important agent for medical practice. In addition to the aforementioned uses, it’s also administered in cases of colitis, neural tube defects, and cognitive dysfunction in the elderly.

The differences between folic acid and folinic acid

Although they’re sometimes used in clinical practice as interchangeable terms, the truth is that there are several differences between folic acid and folinic acid. We’ll discuss them below.

1. Chemical composition

According to the IUPAC nomenclature, folic acid is formulated as follows: (2S) -2 – [(4 – {[(2-amino-4-hydroxypteridin-6-yl) methyl] amino} phenyl) formamide] pentanedioic acid. On the other hand, folinic acid has the following formula: (S) -2- [4 – [(2-amino-5-formyl-4-oxo-5,6,7,8-tetrahydro-1H-pteridin-6- yl) methylamino] benzoyl] aminopentanedioic acid.

This formulation can be dizzying, but the underlying concept is simple: The chemical formula of the two compounds is different. Folinic acid is a reduced form of folic acid, meaning that it has gained electrons during a chemical process.

2. Biochemical pathways and mechanism of action

As indicated by the Statpearls medical portal, unmodified folic acid isn’t biologically active. For this reason, it’s administered in the form of dihydrofolate (DHF) and is converted in the body into tetrahydrofolate (THF, anion of tetrahydrofolic acid already mentioned) thanks to the function of the enzyme dihydrofolate reductase. THF is then transformed into 5-10-methylenetetrahydrofolate.

We’re not going to complicate this explanation any further, but it’s enough for you to know that 5-10-methylenetetrahydrofolate can take 2 organic routes at this point. Methionine synthesis or DNA synthesis. Both processes are essential, as they allow the manufacture of new cells by adding proteins or genetic information.

Folinic acid is an active analog of folic acid, which means that it’s ready to do its job as soon as it enters the human body. In other words, it doesn’t require the action of the enzyme dihydrofolate reductase to convert to THF. In any case, its biological function is the same: To generate nucleic acids, form DNA, and stabilize the genome.

3. Uses

Other essential differences between folic acid and folinic acid lie in their use at the clinical level. Below, we’ll show you their uses separately, and then compare them.

3.1 Uses of folic acid

These are some of the tables in which the administration of folic acid is conceived:

• Folate deficiency: Folic acid is still a vitamin B9, so its intake increases the presence of folate derivatives in the body of patients who, for any reason, have a deficiency. This is one of the few areas in which it has been proven effective in practically all cases.
• High levels of homocysteine in the blood: A high level of homocysteine in the blood can cause damage to the structure of the blood vessels, leading to arteriosclerosis and the risk of heart attacks or strokes. Taking folic acid seems to lower the risk.
• Toxicity caused by the drug methotrexate: This drug is only used to treat cancer and other very serious diseases, as it has potentially fatal side effects. Simultaneous administration of folic acid can reduce some of the symptoms associated with chemotherapy, such as vomiting and nausea.
• Brain defects in the brain and spinal cord: Folic acid ingested during pregnancy reduces the risk of the newborn having serious nervous system failure.

Folate deficiency is the situation in which this supplement is most prescribed, but in the other conditions mentioned, it also seems to obtain positive results. Folic acid is thought to be helpful in treating depression, high blood pressure, cognitive problems in the elderly, and strokes, but more research is required.

3.2 Uses of folinic acid

The Spanish Association of Pediatrics (AEP) cites the following uses for folinic acid:

• Megaloblastic anemia due to folate deficiency: This condition represents a decrease in the number of red blood cells due to a lack of folate, as this compound is essential for the formation of red blood cells. This may be due to a lack of folic acid in the diet, hemolytic anemia, prolonged alcoholism, and the use of certain medications.
• Toxicity during chemotherapy: Like folic acid, folinic acid is used to counteract the effects of methotrexate and pyrimethamine. Leucovorin limits myelosuppression, gastrointestinal toxicity, nephrotoxicity, and neurotoxicity secondary to high doses of methotrexate.

Folinic acid has many other uses beyond those approved by the Food and Drug Administration (FDA). For example, it’s off-label used in the following conditions:

• Breast cancer: Although the FDA hasn’t approved its use in this area due to a lack of evidence, information sources indicate that folinic acid and vitamin B6 can reduce the risk of developing breast cancer.
• Treatment in combination with other chemotherapeutic agents: Folinic acid may help treat some types of cancers, such as non-Hodgkin’s lymphomas.
• Toxoplasmosis: Folinic acid is used in conjunction with pyrimethamine and sulfadoxine in patients with toxoplasmosis who don’t accept the sulfamethoxazole/trimethoprim duo.

3.3 Distinctions in their uses

The use of folic acid and folinic acid is quite similar in the pharmacological field. In any case, folic acid is usually the medicine of choice to avoid problems in the central nervous system during pregnancy, while folinic acid stands out much more as a toxicity reliever during chemotherapy.

4. Formats

Folic acid is administered in most cases in the form of tablets that are taken by mouth. An example of a pharmacological preparation that contains it is Acfol ®, with 5 milligrams of folic acid per tablet.

According to the leaflet of this presentation, the pills are used in the following way:

• Treatment of deficiency: 1 to 3 tablets daily (5 to 15 milligrams of folic acid) divided into 1-2 doses.
• Management of megaloblastic anemia: An oral dose of 5 milligrams per day is recommended for a period of 4 consecutive months, although this concentration can increase up to 15 milligrams per day.
• Prevention of neural tube defects: 1 tablet of 5 milligrams a day for 4 weeks before conception and the first 3 months of pregnancy.

Sources already cited indicate that folinic acid is presented in oral tablet forms, but also in intravenous (IV) injectable solutions. One of its presentations in oral format is Ledeforin ® (15 mg of folinic acid per tablet) and its leaflet shows the following indications:

• Megaloblastic anemia due to folate deficiency: One tablet (15 milligrams of active ingredient) a day for 10-15 days.
• Neutralization of the effect of methotrexate: The precise dose can only be specified by the medical professional.

Intravenous dosing is often the means chosen when the drug is used to mitigate the effects of certain chemotherapeutic agents. The dose of folinic acid depends on the methotrexate administered. For example, to alleviate the effects of 5 to 10 µmol / L of methotrexate, 30 mg / m2 / 6 hours of leucovorin are used intravenously.

Folic acid and folinic acid: Two sides of the same coin

Although we’ve presented you with multiple differences between folic acid and folinic acid, you shouldn’t lose sight of the fact that both are considered respective folates and vitamers, that is, they have very similar functions. The biggest distinction is that folinic acid occurs naturally in plasma and is active, whereas folic acid isn’t.

Although both compounds are very similar, it’s more than clear that folic acid stands out when it comes to preventing fetal nervous problems, and folinic acid to alleviate the side effects of some chemotherapy. As always, the doctor in charge of monitoring the patient will be the one capable of choosing the drug for each condition.