Leucovorin Calcium

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Cat Number

API0232101

CAS Number

1492-18-8

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CAS Number

1492-18-8

EINECS

801-530-2

Storage

Store at room temperature

Synonyms

Folidan; Rescuvolin; Calcii folinas; folinate calcium; Leucovorin calcium preservative free; Lederfolat; Anhydrous calcium folinate

Molecular Formula

C20H21CaN7O7

Molecular Weight

511.5

Smiles

C1C(N(C2=C(N1)N=C(NC2=O)N)C=O)CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-].[Ca+2]

Appearance

Yellowish-white to yellow powder

Melting Point

240-250°C

General Description

Leucovorin calcium is the calcium salt of 5‑formyltetrahydrofolate (folinic acid), a reduced folate that does not require dihydrofolate reductase for conversion to active cofactors. The molecule contains a pteridine ring, a p‑aminobenzoylglutamate moiety, and a formyl group at the N5 position.

Mechanism of Action

Leucovorin serves as an immediate precursor for tetrahydrofolate, bypassing the blocked dihydrofolate reductase step induced by methotrexate. It replenishes reduced folate pools, allowing continued purine and pyrimidine synthesis. In combination with fluorouracil, leucovorin stabilizes the fluorouracil‑thymidylate synthase‑folate ternary complex, enhancing the cytotoxic effect. The calcium salt ensures stability and solubility for both oral and parenteral use.

Application

Leucovorin is indicated as rescue therapy after high‑dose methotrexate to prevent myelosuppression and mucositis. It is also used in combination with fluorouracil for colorectal cancer and in the treatment of folate‑deficiency anemia when oral folic acid is inadequate. In patients with toxoplasmosis, leucovorin is given with pyrimethamine to prevent hematologic toxicity without interfering with the antiparasitic effect.

Using a pharmacogenomic scoring strategy (OligoScore), the authors identified the FDA‑approved drugs leucovorin and dyclonine as potent pro‑oligodendrogenic agents. In neonatal chronic hypoxia (a model of preterm brain injury) and in an adult focal de/remyelination model of multiple sclerosis, both compounds promoted oligodendrocyte progenitor cell differentiation, enhanced lesion repair, and shifted microglia toward a pro‑regenerative phenotype. These findings support repurposing leucovorin and dyclonine for clinical trials in myelin disorders.

Fig. 1 In-silico strategy to generate oligodendroglial-enriched gene sets and their use in pharmacogenomics to identify new hub genes. (Huré JB, et al., 2024)

References

Huré JB, et al. Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair. Nat Commun. 2024;15(1):9837.

The phase III TRIPLETE trial (435 patients with RAS/BRAF wild‑type metastatic colorectal cancer) compared mFOLFOXIRI/panitumumab versus modified FOLFOX/panitumumab as initial therapy. The objective response rate was similar between arms (73% vs. 76%; OR 0.87, P=0.526). No differences were seen in early tumor shrinkage, depth of response, R0 resection rate, or progression‑free survival (12.7 vs. 12.3 months). Intensifying the chemotherapy backbone increased gastrointestinal toxicity without additional benefit.

Fig. 2 Subgroup analyses of the objective response rate according to clinical characteristics of the intention-to-treat population. (Rossini D, et al., 2022)

References

Rossini D, et al. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022;40(25):2878-2888.

Does Leucovorin Calcium require protection from light during storage?

Yes, it is photosensitive. UV light causes photodegradation, converting it to inactive isomers. Store in light-resistant containers, preferably amber glass.

What is the recommended storage temperature for Leucovorin Calcium?

Store at controlled room temperature (15-25°C). Avoid excessive heat above 30°C, which can accelerate oxidation of the tetrahydropteroyl moiety.

Is Leucovorin Calcium stable in solution for injection or oral use?

Reconstituted solutions are stable for up to 24 hours at room temperature when protected from light.

How is the impurity 5-methyltetrahydrofolate (a related folate) monitored?

This process-related impurity is quantified using a stability-indicating HPLC method, ensuring it remains below pharmacopoeial limits.