RESCUVOLIN 15 MG INJECTION

Indications

• Prevention and treatment of methotrexate toxicity
• Enhancement of fluorouracil efficacy in colorectal cancer
• Cerebral folate deficiency
• Supportive therapy in various malignancies

Mechanism of action

Leucovorin functions by providing a pre-reduced form of folate, bypassing the dihydrofolate reductase (DHFR) block caused by methotrexate. It allows continued DNA synthesis in normal cells and competes with methotrexate for transport into cells, reducing its toxic effects. In colorectal cancer treatment, leucovorin stabilizes the complex formed between fluorodeoxyuridylic acid and thymidylate synthase, enhancing the inhibition of DNA synthesis and promoting tumor cell death. It also normalizes levels of 5-methyltetrahydrofolate in the central nervous system in cases of cerebral folate deficiency.

Pharmacodynamics

Leucovorin serves as a biochemical modulator and salvage agent that restores the pool of reduced folates necessary for DNA and RNA synthesis. It effectively prevents or reverses bone marrow suppression and gastrointestinal mucosa inflammation caused by methotrexate. The drug can cross the blood-brain barrier and concentrate in cerebrospinal fluid, affecting rapidly dividing cell populations. Its therapeutic index is wide, although oral absorption is saturable at doses exceeding 25 mg, which may necessitate intravenous administration for higher doses.

Pharmacokinetics

Leucovorin is rapidly absorbed, with peak plasma concentrations occurring within one to two hours after administration. It is distributed widely throughout the body, including the central nervous system. The elimination half-life varies based on the route of administration but is generally short. The drug is primarily excreted unchanged in urine. Its pharmacokinetics may be altered in cases of renal impairment, requiring dose adjustments.

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Rash
• Allergic reactions

Interactions

• Methotrexate
• 5-Fluorouracil
• Anticonvulsants
• Trimethoprim

Precautions

• Monitor for signs of allergic reactions
• Use with caution in elderly patients
• Assess renal function before use

Pregnancy

Leucovorin can be used in pregnancy where the potential benefit justifies the potential risk to the fetus, particularly in cases of folate deficiency.

Breast-feeding

Leucovorin is excreted in breast milk. Caution should be exercised when administering to breastfeeding women.

Storage

Store at room temperature, away from light and moisture. Protect from freezing.

Formulations

• Injectable solution
• Oral tablets

Mechanism of action

Leucovorin is a racemic mixture of diastereoisomers, with the L-isomer (levoleucovorin) being the biologically active moiety. It functions at the molecular level by providing a source of "one-carbon" moieties required for the synthesis of purines and the conversion of deoxyuridylate to thymidylate. Methotrexate acts as a competitive inhibitor of the enzyme DHFR, which normally reduces folic acid to tetrahydrofolate (THF). By providing a pre-reduced form of folate, leucovorin bypasses the DHFR block, allowing for continued DNA synthesis and cellular repair in normal host cells. It also competes with methotrexate for the same active transport processes into the cell, further reducing the drug's toxic impact. In the treatment of colorectal cancer, leucovorin acts as a biochemical sensitizer. 5-FU is metabolized into fluorodeoxyuridylic acid (FdUMP), which binds to the enzyme thymidylate synthase. Leucovorin is converted into 5,10-methylenetetrahydrofolate, which binds to and stabilizes the FdUMP-thymidylate synthase complex. This "ternary complex" locks the enzyme in an inactive state, leading to a more profound inhibition of DNA synthesis and enhanced tumor cell death. In Cerebral Folate Deficiency (CFD), leucovorin serves as a direct substrate to normalize levels of 5-MTHF in the central nervous system, particularly when folate transport across the blood-brain barrier is impaired by autoantibodies or genetic defects. Leucovorin is a derivative of tetrahydrofolic acid, the reduced form of folic acid, which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purines and pyrimidines of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists (eg, methotrexate, pyrimethamine, trimethoprim). It is postulated that in some cancers leucovorin enters and rescues normal cells from the toxic effects of folic acid antagonists, in preference to tumor cells, because of a difference in membrane transport mechanisms; this principle is the basis of high dose methotrexate therapy with leucovorin rescue.

Pharmacodynamics

Leucovorin acts as a biochemical modulator and salvage agent that bypasses metabolic blocks in the folate cycle. Its primary action is to restore the pool of reduced folates necessary for DNA and RNA synthesis, thereby preventing or reversing bone marrow suppression and gastrointestinal mucosa inflammation caused by methotrexate. Systemically, it affects rapidly dividing cell populations and can readily cross the blood-brain barrier to concentrate in the cerebrospinal fluid. The drug's duration of action is relatively short. Leucovorin has a wide therapeutic index, though its oral absorption is saturable at doses exceeding 25 mg, necessitating intravenous administration for higher dose requirements. When used with 5-fluorouracil, it significantly enhances the toxicity of the chemotherapy, which may lead to severe diarrhea and dehydration, particularly in elderly or debilitated patients.