Usage
Uracil, in combination with Tegafur (as Tegafur-uracil), is primarily used as a chemotherapy treatment for various types of cancer. This includes metastatic colorectal cancer, as well as cancers of the breast, stomach, head and neck, and non-small cell lung cancers. It is also used as adjuvant chemotherapy after surgery for colorectal, gastric, and breast cancers. Uracil itself is not an antineoplastic agent but a biomodulator that enhances the effects of Tegafur.
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Pharmacological classification: Antineoplastic, antimetabolite, pyrimidine analog (for its active metabolite 5-FU)
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Mechanism of action: Tegafur is a prodrug that is metabolized into 5-fluorouracil (5-FU), its active form. 5-FU disrupts DNA synthesis, impeding cancer cell growth and replication. Uracil inhibits the enzyme dihydropyrimidine dehydrogenase (DPD), which breaks down 5-FU. By slowing 5-FU degradation, Uracil increases 5-FU concentration and its antitumor effect.
Alternate Names
Uracil is generally referred to by its chemical name. The combination with Tegafur is known as Tegafur-uracil.
- Brand Names: UFToral, Fimer, Furil, Tegracil, Teroful, UFT, UFT ET, Ufur, Unitoral (and others).
How It Works
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Pharmacodynamics: The primary pharmacodynamic effect is through 5-FU, which inhibits DNA and RNA synthesis, leading to cell cycle arrest and apoptosis (programmed cell death) in rapidly dividing cancer cells.
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Pharmacokinetics: Tegafur-uracil is administered orally. Tegafur is rapidly absorbed and converted to 5-FU in the liver. Uracil slows down the breakdown of 5-FU by inhibiting DPD, leading to higher and more sustained 5-FU levels. 5-FU is then further metabolized and excreted primarily through the kidneys.
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Mode of action: At a molecular level, 5-FU, the active metabolite of Tegafur, inhibits thymidylate synthase by forming a stable ternary complex with the enzyme and its cofactor. This blocks the formation of thymidine, a crucial building block for DNA. Consequently, DNA synthesis is interrupted, leading to cell death. 5-FU can also incorporate itself into RNA molecules, disrupting RNA processing and function.
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Receptor binding, enzyme inhibition, or neurotransmitter modulation: The primary mechanism is enzyme inhibition (thymidylate synthase inhibition by 5-FU). Uracil inhibits dihydropyrimidine dehydrogenase (DPD).
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Elimination pathways: Primarily renal excretion, with some hepatic metabolism.
Dosage
Standard Dosage
Tegafur-uracil dosing is typically based on body surface area (BSA), calculated from height and weight.
Adults:
The typical dose is 300-600 mg Tegafur per day (equivalent amount of Tegafur-uracil), taken in 2-3 divided doses every 8 hours, preferably one hour before or after a meal to minimize food interactions. When combined with calcium folinate, the dose of Tegafur is often 300mg/m2 per day, also given in three divided doses with Calcium Folinate 75mg/day. For cervical cancer, 600mg/day in 2-3 divided doses may be prescribed.
Children:
The safety and efficacy of Tegafur-Uracil in children and adolescents have not been established. Use is not recommended in pediatric patients.
Special Cases:
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Elderly Patients: Caution is advised, starting with lower doses and close monitoring for toxicity due to potential age-related decline in organ function.
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Patients with Renal Impairment: Dose adjustments may be necessary depending on creatinine clearance.
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Patients with Hepatic Dysfunction: Dose adjustments are likely required due to the liver’s role in metabolizing Tegafur. Close monitoring of liver function tests is crucial.
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Patients with Comorbid Conditions: Careful consideration and dose adjustments might be necessary in patients with heart conditions, bone marrow suppression, or infections.
Clinical Use Cases
Tegafur-uracil, along with other chemotherapeutic agents, is used in various oncology settings. Dosing is generally consistent with the standard recommendations, potentially adjusted based on individual patient characteristics and combination therapies. Specific protocols may vary based on the type and stage of cancer.
Dosage Adjustments
Dosage modifications are based on patient factors like renal/hepatic function, other medical conditions, and observed adverse effects. Dose reductions or treatment interruptions might be necessary to manage toxicity. Genetic testing for DPD deficiency is crucial as these patients are at very high risk of severe toxicity from 5-FU.
Side Effects
Common Side Effects:
Diarrhea, nausea, vomiting, fatigue, stomatitis (mouth sores), anorexia (loss of appetite), increased risk of infections, bruising or bleeding (due to myelosuppression - bone marrow suppression), anemia, skin rash, changes in skin and nails, alopecia (hair loss).
Rare but Serious Side Effects:
Severe myelosuppression (neutropenia, thrombocytopenia), severe diarrhea, hand-foot syndrome (palmar-plantar erythrodysesthesia), hepatotoxicity (liver damage including fulminant hepatitis - severe and sudden liver failure), severe skin reactions, cardiotoxicity, neurotoxicity.
Long-Term Effects:
Chronic myelosuppression, secondary malignancies (risk increases with long-term exposure to chemotherapy), permanent organ damage (e.g., liver, kidney, heart).
Adverse Drug Reactions (ADR):
Severe myelosuppression, hepatotoxicity, severe diarrhea, hypersensitivity reactions, Stevens-Johnson syndrome (severe skin reaction), toxic epidermal necrolysis (severe life-threatening skin reaction).
Contraindications
- Hypersensitivity to Tegafur, Uracil, or 5-FU.
- Severe bone marrow suppression.
- Pregnancy and breastfeeding.
- DPD deficiency (genetic or acquired).
- Concomitant use with sorivudine.
Drug Interactions
- Anticoagulants (e.g., Warfarin): Increased risk of bleeding.
- Antiepileptics (e.g., Phenytoin): Increased Phenytoin levels.
- Cimetidine: Increased Uracil levels.
- Folic acid: May reduce the efficacy of 5-FU.
- Other myelosuppressive agents: Increased risk of bone marrow suppression.
- Live vaccines: Reduced effectiveness of vaccines due to immunosuppression.
Pregnancy and Breastfeeding
Tegafur-uracil is contraindicated during pregnancy and breastfeeding. 5-FU is known to be teratogenic (can cause birth defects) and potentially harmful to the developing fetus. Uracil can also be transferred to breast milk.
Drug Profile Summary
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Mechanism of Action: Tegafur is metabolized into 5-FU, inhibiting DNA/RNA synthesis, leading to cancer cell death. Uracil enhances 5-FU’s action by inhibiting its breakdown.
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Side Effects: Diarrhea, nausea, vomiting, stomatitis, myelosuppression, hepatotoxicity.
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Contraindications: Hypersensitivity, severe bone marrow suppression, pregnancy, breastfeeding, DPD deficiency.
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Drug Interactions: Anticoagulants, antiepileptics, cimetidine, folic acid.
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Pregnancy & Breastfeeding: Contraindicated.
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Dosage: 300-600 mg/day of Tegafur, divided doses, with or without calcium folinate.
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Monitoring Parameters: Complete blood count (CBC) with differential, liver function tests (LFTs), renal function tests.
Popular Combinations
- Tegafur-uracil + Calcium Folinate: Calcium folinate enhances the cytotoxic effect of 5-FU, improving treatment efficacy.
Precautions
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General Precautions: Evaluate patients for adequate bone marrow, liver, and kidney function before and during treatment. Monitor for signs of toxicity.
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Specific Populations: Avoid in pregnancy and breastfeeding. Use with caution in the elderly and in patients with organ dysfunction.
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Lifestyle Considerations: Patients should avoid alcohol and be cautious with driving or operating machinery due to potential fatigue and other side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Uracil in Tegafur-uracil?
A: Uracil is not dosed independently but is given as a fixed combination with Tegafur. Tegafur is usually dosed at 300-600mg per day or 300 mg/m2/day, taken in 2-3 divided doses every 8 hours when taken with or without calcium folinate.
Q2: How does Uracil contribute to the efficacy of Tegafur?
A: Uracil inhibits DPD, the enzyme responsible for 5-FU degradation, resulting in increased 5-FU concentration and enhanced antitumor activity.
Q3: What are the major side effects of Tegafur-uracil?
A: Common side effects include diarrhea, nausea, vomiting, myelosuppression, stomatitis, and fatigue. Serious side effects can include hepatotoxicity and severe myelosuppression.
Q4: What are the absolute contraindications for Tegafur-uracil?
A: Contraindications include hypersensitivity, severe bone marrow suppression, pregnancy, breastfeeding, DPD deficiency, and concomitant use with sorivudine.
Q5: How should Tegafur-uracil be administered?
A: Orally, one hour before or after meals, usually in 2-3 divided doses every 8 hours.
Q6: How is Tegafur-uracil dose adjusted in patients with renal impairment?
A: Dose adjustment may be necessary based on creatinine clearance and should be determined by the treating oncologist.
Q7: Can Tegafur-uracil be used in children?
A: Safety and efficacy in children and adolescents have not been established, so it is generally not recommended.
Q8: What monitoring parameters are essential during Tegafur-uracil therapy?
A: Regular CBC with differential, LFTs, and renal function tests are crucial to monitor for toxicity.
Q9: What should patients be advised about lifestyle while on Tegafur-uracil?
A: Avoid alcohol and use caution when driving or operating machinery due to potential fatigue and other side effects.
Q10: Why is DPD testing important before starting Tegafur-uracil?
A: Patients with DPD deficiency are at high risk for severe toxicity from 5-FU, the active metabolite of Tegafur. DPD testing helps identify these patients and prevent potentially life-threatening complications.
