1. Clinical Overview
Tegafur + Uracil is a fixed-dose oral fluoropyrimidine combination used primarily in the treatment of gastrointestinal cancers. Tegafur is a prodrug of 5-fluorouracil (5-FU), and uracil competitively inhibits the enzyme dihydropyrimidine dehydrogenase (DPD), which degrades 5-FU, thereby prolonging its half-life and enhancing its antitumor activity. This combination allows for convenient oral administration with a more favorable pharmacokinetic profile compared to intravenous 5-FU.
| Onset | Duration | Bioavailability |
|---|---|---|
| Therapeutic effects are typically observed after several weeks of therapy, as it is a cytotoxic agent requiring multiple cell cycles for tumor response. | The cytotoxic effect is prolonged due to the uracil-induced inhibition of DPD, with significant plasma concentrations of 5-FU maintained for up to 12-24 hours post-dose. | Tegafur bioavailability is approximately 52-58% after oral administration. The presence of uracil does not significantly alter tegafur absorption but profoundly affects 5-FU metabolism. |
2. Mechanism of Action
Tegafur is a prodrug that is converted hepatically to the active metabolite 5-fluorouracil (5-FU). 5-FU exerts its cytotoxic effect through two primary mechanisms: 1) Inhibition of thymidylate synthase (TS) by its metabolite fluorodeoxyuridine monophosphate (FdUMP), which disrupts DNA synthesis. 2) Incorporation of its metabolites (FUTP, FdUTP) into RNA and DNA, leading to dysfunctional nucleic acid synthesis and cell death. Uracil, a natural pyrimidine base, competitively inhibits the enzyme dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. This inhibition results in sustained plasma and tumor tissue concentrations of 5-FU, enhancing its efficacy.
3. Indications & Uses
- Adjuvant therapy for Stage III colon cancer (post-surgery)
- Palliative treatment of metastatic colorectal cancer
- Palliative treatment of advanced gastric (stomach) cancer
4. Dosage & Administration
Adult Dosage: Standard dose: Tegafur 300-400 mg/m²/day (in divided doses) + Uracil in a fixed 1:4 molar ratio. Common regimen: 2 capsules of Tegafur 100mg + Uracil 224mg, taken orally three times daily (total 600 mg tegafur/day) for 28 days, followed by a 7-day rest period (35-day cycle). Dose is based on body surface area (BSA).
Administration: Take capsules with a full glass of water, within 1 hour after a meal to reduce gastrointestinal upset. Do not crush or chew. Doses should be spaced evenly throughout the day (e.g., every 8 hours).
5. Side Effects
Common side effects may include:
- Anorexia, nausea, vomiting
- Diarrhea
- Stomatitis (mouth sores)
- Hyperpigmentation of skin/nails
- Fatigue, malaise
- Mild myelosuppression (leukopenia, anemia)
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Warfarin and other Coumarin Anticoagulants | Increased anticoagulant effect and risk of bleeding due to protein binding displacement and possible reduced metabolism. | Major |
| Phenytoin | Increased phenytoin levels and risk of toxicity. Tegafur may inhibit CYP2C9. | Major |
| Leucovorin (Calcium Folinate) | Potentiates the cytotoxic effect of 5-FU by stabilizing the ternary complex with thymidylate synthase. Used therapeutically but requires careful monitoring for increased toxicity. | Moderate |
| Allopurinol | May decrease the efficacy of 5-FU by interfering with its activation pathway. Generally not co-administered. | Moderate |
| Live Vaccines (e.g., MMR, Varicella, Yellow Fever) | Risk of disseminated vaccine-induced infection due to immunosuppression. Contraindicated. | Major |
| CYP2A6 Inhibitors (e.g., Methoxsalen, Tranylcypromine) | May decrease conversion of tegafur to 5-FU, reducing efficacy. | Moderate |
| CYP2A6 Inducers (e.g., Rifampicin) | May increase conversion of tegafur to 5-FU, potentially increasing toxicity. | Moderate |
7. Patient Counselling
- DO take the capsules exactly as prescribed, with food and water.
- DO maintain good oral hygiene to reduce risk of mouth sores.
- DO use sunscreen and protective clothing as the drug can increase photosensitivity.
- DO report any fever, chills, sore throat, or signs of infection immediately.
- DONT crush, chew, or break the capsules.
- DONT take a missed dose if it is almost time for the next dose. Do not double dose.
- DONT receive any vaccinations without consulting your oncologist.
- DONT become pregnant or father a child while on this medication. Use effective contraception.
8. Toxicology & Storage
Overdose: Exacerbation of all expected toxicities: Severe, life-threatening myelosuppression (neutropenia, thrombocytopenia), intractable diarrhea and vomiting leading to dehydration, severe mucositis, neurotoxicity (altered mental status, cerebellar ataxia), and cardiotoxicity.
Storage: Store below 30°C. Protect from light and moisture. Keep in the original blister pack or container. Keep out of reach of children and pets. Do not use after the expiry date printed on the pack.