Usage
- Doxifluridine is primarily prescribed for the treatment of advanced gastric cancer, often in combination with other chemotherapeutic agents. It is also used in the adjuvant treatment of several cancers, including stomach, colon, rectum, breast, uterine, cervix, and bladder cancer. It has shown some antibacterial activity against Staphylococcus aureus, including methicillin-resistant strains, but this use is not clinically established.
- Pharmacological Classification: Antineoplastic antimetabolite; pyrimidine analog prodrug of 5-fluorouracil (5-FU).
- Mechanism of Action: Doxifluridine acts as a prodrug of 5-FU. It is converted to 5-FU within the body, primarily in tumor tissues with high thymidine phosphorylase activity. 5-FU exerts its anticancer effects by inhibiting thymidylate synthase, a key enzyme in DNA synthesis. This leads to a depletion of thymidine, disrupting DNA replication and repair, and ultimately causing cell death.
Alternate Names
- 5′-Deoxy-5-fluorouridine
- 5′-dFUrd
- Ro 21-9738
How It Works
- Pharmacodynamics: Doxifluridine’s effects are primarily due to its conversion to 5-FU. 5-FU inhibits thymidylate synthase, leading to DNA damage, cell cycle arrest, and apoptosis, particularly in rapidly dividing cells like cancer cells.
- Pharmacokinetics: Doxifluridine is administered orally. It is well-absorbed and converted to 5-FU by thymidine phosphorylase, predominantly in tissues with high enzyme activity, including tumor cells and the intestinal tract. The pharmacokinetics of doxifluridine itself are not well-defined in available resources. The elimination pathways for 5-FU involve hepatic metabolism primarily, with a small amount of unchanged 5-FU being excreted in the urine.
- Mode of Action: Doxifluridine is converted into 5-fluorouracil. 5-FU is then metabolized to various active forms, including 5-fluoro-2’-deoxyuridine-5’-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase. This enzyme is crucial for the synthesis of thymidine monophosphate (dTMP), a necessary building block for DNA. The resulting dTMP depletion disrupts DNA synthesis and repair processes, leading to cell cycle arrest and apoptosis.
- Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: The primary mechanism involves enzyme inhibition (thymidylate synthase) by FdUMP, a metabolite of 5-FU.
- Elimination Pathways: Primarily hepatic metabolism, with a small fraction of unchanged 5-FU excreted renally.
Dosage
Doxifluridine dosage regimens are not standardized and vary considerably based on research context and clinical trials. The information below reflects reported usages but does not constitute definitive clinical guidance.
Standard Dosage
Adults:
- Limited data available; studied dosages have ranged from 800 mg/day to 1200 mg/day orally, often in combination with other chemotherapeutic agents, such as irinotecan. Other research, in different applications, has used dosages between 1 and 32 mg/kg.
- One regimen employed sequential treatment with irinotecan and doxifluridine, with doxifluridine administered orally at 800 mg/day for specific periods within a 5-week cycle.
- Another study used doses ranging from 800 to 1200 mg in combination with irinotecan.
- A study for ovarian cancer utilized 3000 mg/m² administered intravenously for 5 consecutive days, repeated every 3 weeks.
Children:
- Pediatric dosage guidelines are not established. Use in children requires careful consideration and should be guided by expert opinion in a research setting.
Special Cases:
- Elderly Patients: Limited specific guidance is available for elderly patients. Careful monitoring is necessary, and dose adjustments may be needed based on individual tolerance and organ function. One study used oral doxifluridine in elderly patients with metastatic colorectal cancer at an initial daily dose of 2250 mg for 4 consecutive days each week, with dose reductions to 1500 mg if grade 2 or higher toxicity occurred.
- Patients with Renal Impairment: Dose modifications are advised in moderate renal impairment. Use is not recommended in severe renal impairment.
- Patients with Hepatic Dysfunction: Doxifluridine should be used with caution in patients with hepatic impairment due to the potential for increased toxicity from its metabolite, 5-FU.
- Patients with Comorbid Conditions: Careful monitoring and dose adjustments may be necessary based on individual patient circumstances.
Clinical Use Cases
- Dosage recommendations for specific medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not defined in available literature.
Dosage Adjustments
- Dosage adjustments should be carefully considered based on individual patient factors, such as renal or hepatic dysfunction, metabolic disorders, or genetic polymorphisms affecting drug metabolism. However, specific guidelines are not provided in existing research.
Side Effects
Common Side Effects
- Diarrhea (can be dose-limiting)
- Nausea and vomiting
- Anorexia
- Fatigue
- Alopecia (hair loss)
- Stomatitis (oral sores)
- Myelosuppression (bone marrow suppression)
Rare but Serious Side Effects
- Severe diarrhea
- Neutropenia (low white blood cell count) increasing the risk of infections
- Thrombocytopenia (low platelet count) increasing the risk of bleeding
- Neurotoxicity, including central nervous system effects
Long-Term Effects
- Chronic complications from prolonged use have not been well characterized but may include persistent myelosuppression and potential for secondary malignancies associated with 5-FU.
Adverse Drug Reactions (ADR)
- Severe myelosuppression
- Neurotoxicity
- Severe diarrhea
Contraindications
- Hypersensitivity to doxifluridine or 5-FU
- Severe bone marrow suppression
- Active serious infections
- Pregnancy and breastfeeding (likely contraindicated due to the potential for fetal harm based on the effects of 5-FU)
Drug Interactions
- Limited data available. Potential interactions with drugs affecting 5-FU metabolism or those with overlapping toxicities (e.g., other myelosuppressive agents).
- Increased anticoagulant effect of warfarin.
- Potential interactions with phenytoin.
- Interactions with commonly prescribed medications, OTC drugs, supplements, and lifestyle factors need further investigation.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Likely contraindicated due to potential fetal harm (based on the known teratogenic effects of 5-FU). Avoid pregnancy during treatment and for a period after treatment as advised by the physician.
- Breastfeeding: Contraindicated. Doxifluridine is excreted in breast milk and can cause harm to the nursing infant.
Drug Profile Summary
- Mechanism of Action: Pyrimidine analog antimetabolite, prodrug of 5-FU; inhibits thymidylate synthase, disrupting DNA synthesis.
- Side Effects: Diarrhea, nausea, vomiting, anorexia, fatigue, alopecia, stomatitis, myelosuppression, neurotoxicity, increased infection risk.
- Contraindications: Hypersensitivity, severe bone marrow suppression, active serious infections, pregnancy, breastfeeding.
- Drug Interactions: Limited data; potential interactions with drugs affecting 5-FU metabolism or with overlapping toxicities (e.g., warfarin, phenytoin).
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Variable and dependent on clinical context. Reported use ranges from 800 mg/day to 1200 mg/day orally, often in combination with other chemotherapy agents. Intravenous administration of 3000mg/m² for 5 days every 3 weeks has also been studied.
- Monitoring Parameters: Complete blood count (CBC) to monitor for myelosuppression, liver function tests, renal function tests, and monitoring for signs of neurotoxicity and gastrointestinal toxicity.
Popular Combinations
- Irinotecan: Used sequentially or concurrently with doxifluridine in some studies for metastatic colorectal and gastric cancer. Rationale: Potential for synergistic anticancer effects.
Precautions
- General Precautions: Careful pre-screening is required, assessing for pre-existing medical conditions such as bone marrow suppression, hepatic or renal dysfunction, and active infections.
- Specific Populations: Doxifluridine should be avoided in pregnant and breastfeeding women. Caution is necessary in elderly patients. Safety and effectiveness in children have not been established.
- Lifestyle Considerations: Alcohol should be avoided during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Doxifluridine?
A: There is no universally recommended dosage for Doxifluridine. Dosing regimens vary significantly based on the specific clinical trial or research context and the type of cancer being treated. Consult updated research literature and clinical trial protocols for the most accurate and up-to-date dosage information.
Q2: What is the mechanism of action of Doxifluridine?
A: Doxifluridine is a prodrug converted to 5-fluorouracil (5-FU). 5-FU inhibits thymidylate synthase, an enzyme essential for DNA synthesis. This leads to thymidine depletion, disrupting DNA replication and leading to cell death.
Q3: What are the most common side effects of Doxifluridine?
A: Common side effects include diarrhea (which can be dose-limiting), nausea, vomiting, anorexia, fatigue, alopecia, stomatitis, and myelosuppression.
Q4: Is Doxifluridine safe to use during pregnancy or breastfeeding?
A: No. Doxifluridine is contraindicated in both pregnancy and breastfeeding due to the risk of fetal harm and its excretion in breast milk.
Q5: What are the key drug interactions to be aware of with Doxifluridine?
A: Data on drug interactions are limited. Potential interactions exist with drugs impacting 5-FU metabolism or with overlapping toxicities. Warfarin’s anticoagulant effect can be increased, and potential interactions with phenytoin exist. Further research is needed to fully understand the drug interaction profile of Doxifluridine.
Q6: What are the contraindications for Doxifluridine?
A: Contraindications include hypersensitivity to Doxifluridine or 5-FU, severe bone marrow suppression, active serious infections, pregnancy, and breastfeeding.
Q7: How should Doxifluridine be administered?
A: Doxifluridine is typically administered orally. Intravenous administration has also been studied. Specific administration details are highly dependent on the clinical trial or research context.
Q8: What monitoring parameters are important during Doxifluridine treatment?
A: Monitoring should include complete blood counts (CBCs) to assess for myelosuppression, liver function tests, renal function tests, and observation for signs of neurotoxicity and gastrointestinal toxicity.
Q9: Are there any special considerations for elderly patients receiving Doxifluridine?
A: Elderly patients may require careful monitoring and potential dose adjustments due to age-related physiological changes and potential decreased drug tolerance.
Q10: Can Doxifluridine be used to treat infections?
A: While Doxifluridine has shown some in vitro and in vivo activity against certain bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), it is not currently clinically approved for use as an antibacterial agent. Its primary indication remains as a chemotherapy agent.
