FLUROXAN 500 INJECTION

Indications

• Colorectal cancer
• Breast cancer
• Gastric cancer
• Pancreatic cancer
• Head and neck cancers
• Basal cell carcinoma

Dosage

Adults: Refer to the BNF for specific

Mechanism of action

The exact mechanism of action of 5-fluorouracil is not completely understood, but it primarily involves the binding of its active form, deoxyribonucleotide (FdUMP), with the folate cofactor N5–10-methylenetetrahydrofolate to thymidylate synthase (TS), forming a covalent complex. This inhibits the conversion of uracil to thymidine, thus hindering DNA and RNA synthesis, leading to cell death. Additionally, 5-FU can be incorporated into RNA, replacing uridine triphosphate (UTP), which disrupts RNA processing and protein synthesis.

Pharmacodynamics

5-Fluorouracil is categorized as an anti-metabolite that mimics the structure of pyrimidines, effectively disrupting the synthesis of nucleic acids during the S phase of the cell cycle. By inhibiting thymidylate synthase, 5-FU prevents the incorporation of thymidine into DNA, thereby impeding normal cell division and growth, which is particularly beneficial in the treatment of rapidly dividing cancer cells.

Pharmacokinetics

Following administration, 5-fluorouracil is rapidly absorbed and metabolized in the liver. Its bioavailability varies and is influenced by the route of administration. The drug undergoes extensive first-pass metabolism, yielding various metabolites, with only a small fraction reaching systemic circulation. The elimination half-life of 5-FU is short, typically around 10 to 20 minutes, necessitating continuous infusion or frequent dosing in therapeutic regimens. Renal excretion plays a significant role in the elimination of its metabolites.

Contra-indications

• Hypersensitivity to 5-fluorouracil or any of its components
• Severe bone marrow suppression
• Pregnancy

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Stomatitis
• Hand-foot syndrome
• Bone marrow suppression
• Alopecia
• Neurotoxicity

Interactions

• Increased risk of toxicity when used with other myelosuppressive agents
• May interact with drugs that affect liver enzymes involved in its metabolism

Precautions

• Use with caution in patients with renal or hepatic impairment
• Monitor for signs of infection due to bone marrow suppression
• Use with caution in elderly patients

Pregnancy

5-fluorouracil is contraindicated in pregnancy due to potential teratogenic effects.

Breast-feeding

It is not known whether 5-fluorouracil is excreted in human milk, caution is advised when administering to breastfeeding women.

Storage

Store in a cool, dry place away from light. Protect from moisture.

Formulations

• Injection for intravenous use
• Topical cream

Mechanism of action

The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. 5-FU requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. Several routes are available for the formation of the 5'-monophosphate nucleotide (F-UMP) in animal cells. 5-FU may be converted to fluorouridine by uridine phosphorylase and then to F-UMP by uridine kinase, or it may react directly with 5-phosphoribosyl-1-pyrophosphate (PRPP), in a reaction catalyzed by ... orotate phosphoribosyl transferase, to form F-UMP. Many metabolic pathways are available to F-UMP, including incorporation in to RNA. A reaction sequence crucial for antineoplastic activity involves reduction of the diphosphate nucleotide by the enzyme ribonucleoside diphosphate reductase to the deoxynucleotide level and the eventual formation of 5-fluoro-2'-deoxyuridine-5'-phosphate (F-dUMP). 5-FU also may be converted directly to the deoxyriboside 5-FUdR by the enzyme thymidine phosphorylase and further to F-dUMP, a potent inhibitor of thymidylate synthesis, by thymidine kinase ... The interaction between F-dUMP and the enzyme thymidylate synthase leads to depletion of TTP, a necessary constituent of DNA ... The folate cofactor, 5,10-methylenetetrahydrofolate, and F-dUMP form a covalently bound ternary complex with the enzyme. The inhibitory complex resembles the transition state formed during the normal enzymatic reaction when dUMP is converted to thymidylate. Although the physiological complex progresses to the synthesis of thymidylate by transfer of the methylene group and 2 hydrogen atoms from folate to dUMP, this reaction is blocked in the inhibitory complex by the stability of the fluorine carbon bond on F-dUMP; sustained inhibition of the enzyme results ... Although the precise mechanisms of action of fluorouracil have not been fully elucidated, the main mechanism is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5-10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from uracil, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis. Fluorouracil is an antimetabolite of the pyrimidine analog type. Fluorouracil is considered to be cell cycle-specific for the S phase of cell division. Activity results from its conversion to an active metabolite in the tissues, and includes inhibition of DNA and RNA synthesis. There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and take up fluorouracil at a more rapid rate. The catabolic metabolism of fluorouracil results in degradation products (eg, CO2 , urea, (alpha)-fluoro-(beta)-alanine) which are inactive.

Pharmacodynamics

Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand.