Fluorouracil
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| Clinical data | |
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| Routes of administration | Intravenous (infusion or bolus) and topical |
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| Pharmacokinetic data | |
| Bioavailability | 28 to 100% |
| Protein binding | 8 to 12% |
| Metabolism | Intracellular and hepatic (CYP-mediated) |
| Elimination half-life | 10 to 20 minutes |
| Excretion | Renal |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.078 |
| Chemical and physical data | |
| Formula | C4H3FN2O2 |
| Molar mass | 130.077 g/mol g·mol−1 |
Fluorouracil (5-FU) is a drug that is used in the treatment of cancer. It belongs to the family of drugs called antimetabolites. It is a pyrimidine analog. It is typically administered with Leucovorin.
Uses
The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of the pyrimidine thymine-which is important in DNA replication [1]. Thymidylate synthase methylates deoxyuracilmonophoshate (dUMP) into deoxythyminemonophosphate (dTMP).
Like many anti-cancer drugs, 5-FU's effects are felt systemwide but falls most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery -- cancer cells, for instance.
Some of its principal use is in colorectal cancer and pancreatic cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs are a recent addition).
5-FU is also used in ophthalmic surgery, specifically to augment trabeculectomy (an operation performed to lower the intraocular pressure in patients with glaucoma) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scaring at the trabeculectomy site is the main cause for failure of the surgery.
Fluorouracil can be used topically (as a cream) for treating actinic (solar) keratoses and some types of basal cell carcinomas of the skin. It is often referred to by its trade names Efudix, Carac or Fluoroplex.
Mode of action
As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the exosome complex, an exoribonuclease complex of which the activity is essential for cell survival.
Capecitabine is a prodrug that is converted into 5-FU in the tissues. It can be administered orally.
Adverse effects
Side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity.
When using a pyrimidine-based drug, all users must be aware that there is a genetic inability to metabolize them. Current theory points to nearly 8% of the population suffering what is termed DPD deficiency. There are laboratory tests to determine the relative activity of the DPD enzyme, but these tests are now commercially available. Thousands of patients eagerly await the increased availability of clinical DPD testing. Work in this sector has been carried out in both the U.S. and Europe. Currently there is only two labs to offer DPD testing, Coventry Diagnostics and DNAVision (Belgium). It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.
External links
- Cancerbackup.org.uk – Fluorouracil's use in cancer
- DermnetNZ – Fluorouracil cream
- 5-Fluorouracile - DPYD genetic test - DNAVision
- 5-Fluorouracile - DPD Enzyme Deficiency test
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