indication

For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid.

pharmacology

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.

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.

toxicity

LD₅₀=230mg/kg (orally in mice)

biotransformation

Hepatic

absorption

28-100%

half life

10-20 minutes

route of elimination

Seven percent to 20% of the parent drug is excreted unchanged in the urine in 6 hours; of this over 90% is excreted in the first hour. The remaining percentage of the administered dose is metabolized, primarily in the liver.

drug interactions

Acenocoumarol: The antineoplasic agent, fluorouracil, may increase the anticoagulant effect of acenocoumarol.

Anisindione: The antineoplasic agent, fluorouracil, may increase the anticoagulant effect of anisindione.

Dicumarol: The antineoplasic agent, fluorouracil, may increase the anticoagulant effect of dicumarol.

Ethotoin: Fluorouracil increases the effect of hydantoin

Fosphenytoin: Fluorouracil increases the effect of hydantoin

Mephenytoin: Fluorouracil increases the effect of hydantoin

Metronidazole: Risk of 5-FU toxicity when associated with metronidazole

Phenytoin: Fluorouracil increases the effect of hydantoin

Tamoxifen: Fluorouracil may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Fluorouracil is initiated, discontinued or dose changed.

Temsirolimus: Co-administration of Temsirolimus and Fluorouracil may result in serious adverse drug reactions.

Tolbutamide: Fluorouracil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Fluorouracil is initiated, discontinued or dose changed.

Torasemide: Fluorouracil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluorouracil is initiated, discontinued or dose changed.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Trimethoprim: The strong CYP2C9 inhibitor, Fluorouracil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluorouracil is initiated, discontinued or dose changed.

Voriconazole: Fluorouracil, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if fluorouracil is initiated, discontinued or dose changed.

Warfarin: Fluorouracil, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if fluorouracil is initiated, discontinued or dose changed.

Zafirlukast: Fluorouracil, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if fluorouracil is initiated, discontinued or dose changed.