Fluorouracil

Synonyms :
5-Fluoracil, 5-Fluoropyrimidine-2,4-dione, 5-Fluorouracil, 5-Fluracil, 5-FU, Fluoro Uracil, Fluorouracil, Fluorouracilo, Fluorouracilum, Fluouracil, FU

Status : approved

Category

Immunosuppressive Agents

Therapeutic Classification

ANTIMETABOLITES

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
ANTIMETABOLITES
Antimetabolites

Description

A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [PubChem]

Used

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.

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.

Dosage

Form Route Strength
Solution topical 0.5 %
Injection intravenous 2.5 g/50mL
Injection intravenous 5 g/100mL
Injection intravenous 50 mg/mL
Liquid intravenous 500 mg
Cream topical 5 mg/g
Cream topical 2 g/40g
Cream topical 5 %
Cream topical 10 mg/g
Cream topical 1 %
Cream topical 50 mg/g
Injection, solution intravenous 50 mg/mL
Solution topical 20 mg/mL
Solution topical 50 mg/mL
Liquid intravenous 50 mg
Solution intravenous 5 g
Solution intravenous 50 mg
Cream topical .04 g/g

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.

Toxic Effect

LD50=230mg/kg (orally in mice)

Metabolism

Hepatic. The catabolic metabolism of fluorouracil results in degradation products ( e.g., CO2, urea and α-fluoro-ß-alanine) which are inactive.

Absorption

28-100%

Half Life

10-20 minutes

Protein Binding

8-12%

Elimination Route

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.

Chemical Classification

This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.

Halopyrimidines

Organic compounds

Organoheterocyclic compounds

Diazines

Pyrimidines and pyrimidine derivatives

Chemical Name

5-Fluoracil

Brands

name Dosage form Country
Actikerall solution Canada
Adrucil solution Canada
Adrucil injection US
Adrucil injection US
Adrucil injection US
Adrucil Inj 50mg/ml liquid Canada
Carac cream US
Carac cream US
Efudex cream US
Efudex Crm 5% cream Canada
Fluoroplex cream US
Fluoroplex Cream 1% cream Canada
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil solution US
Fluorouracil solution US
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil cream US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil injection, solution US
Fluorouracil solution US
Fluorouracil solution US
Fluorouracil Inj 50mg/ml liquid Canada
Fluorouracil Injection solution Canada
Fluorouracil Injection solution Canada
Fluorouracil Injection USP solution Canada
Tolak cream US

Drug Drug Interactions

  •  Bosentan  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan.
  •  Carvedilol  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.
  •  Cimetidine  : May increase the serum concentration of Fluorouracil (Systemic).
  •  Clozapine  : Myelosuppressive Agents may enhance the adverse/toxic effect of Clozapine. Specifically, the risk for agranulocytosis may be increased.
  •  Denosumab  : May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
  •  Dronabinol  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol.
  •  Dronabinol  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol.
  •  Fosphenytoin  : Fluorouracil (Systemic) may increase the serum concentration of Fosphenytoin.
  •  Gemcitabine  : May increase the serum concentration of Fluorouracil (Systemic).
  •  Lacosamide  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide.
  •  Leflunomide  : Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
  •  Metamizole  : May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
  •  Natalizumab  : Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
  •  Ospemifene  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene.
  •  Parecoxib  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of parecoxib.
  •  Phenytoin  : Fluorouracil (Systemic) may increase the serum concentration of Phenytoin.
  •  Pimecrolimus  : May enhance the adverse/toxic effect of Immunosuppressants.
  •  Ramelteon  : CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon.
  •  Roflumilast  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Sipuleucel-T  : Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
  •  Sorafenib  : May decrease the serum concentration of Fluorouracil (Systemic). Sorafenib may increase the serum concentration of Fluorouracil (Systemic).
  •  Tofacitinib  : Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
  •  Trastuzumab  : May enhance the neutropenic effect of Immunosuppressants.

Food Interactions

  • Vitamin B1 needs increased with long term use.

Calculated Property

kind Value Source
logP -0.58 ALOGPS
logS -1.4 ALOGPS
Water Solubility 5.86e+00 g/l ALOGPS
logP -0.66 ChemAxon
IUPAC Name 5-fluoro-1,2,3,4-tetrahydropyrimidine-2,4-dione ChemAxon
Traditional IUPAC Name fluorouracil ChemAxon
Molecular Weight 130.0772 ChemAxon
Monoisotopic Weight 130.017855555 ChemAxon
SMILES FC1=CNC(=O)NC1=O ChemAxon
Molecular Formula C4H3FN2O2 ChemAxon
InChI InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9) ChemAxon
InChIKey InChIKey=GHASVSINZRGABV-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 58.2 ChemAxon
Refractivity 26.17 ChemAxon
Polarizability 9.46 ChemAxon
Rotatable Bond Count 0 ChemAxon
H Bond Acceptor Count 2 ChemAxon
H Bond Donor Count 2 ChemAxon
pKa (strongest acidic) 7.76 ChemAxon
pKa (strongest basic) -8 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 1 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Thymidylate synthase : in Human
  • DNA : in Human
  • RNA : in Human