Fluorouracil
Thymidylate synthase (TS) inhibition
Generic Name
Thymidylate synthase (TS) inhibition
Mechanism
- Thymidylate synthase (TS) inhibition: Metabolized to 5-fluoro-5′-deoxyuridine monophosphate (FdUMP), forms a covalent ternary complex with TS and 5,10‑methylene‑tetrahydrofolate, blocking dTMP synthesis.
- DNA incorporation: Active triphosphate metabolite (FdUTP) is mistakenly incorporated into DNA, leading to strand breaks.
- Indirect apoptosis: Disruption of nucleotide pools and DNA damage triggers cell death, preferentially affecting rapidly dividing tumor cells.
Pharmacokinetics
| Feature | Details |
| Absorption | Poor oral bioavailability (~5 %); typically given intravenously or topically. |
| Distribution | Wide tissue distribution; large volume of distribution (~0.6 L/kg). Highly protein‑bound (~30 %). |
| Metabolism | Primarily cytosolic thymidine phosphorylase and dihydropyrimidine dehydrogenase (DPD) in liver/endothelial cells. |
| Elimination | Renal (≈15 %) and hepatic via metabolites (FdUMP, FdUTP, 5‑fluorouracil). Half‑life: 20–30 min IV; topical preparations have longer local retention. |
| Drug Interactions |
• DPD inhibitors (e.g., 5‑fluorouracil, capecitabine) compete for metabolism. • Methotrexate prolongs half‑life when co‑administered. |
Indications
- Solid tumors:
- Colorectal cancer (neoadjuvant/adjuvant and palliative).
- Head and neck squamous cell carcinoma (adjunctive chemoradiation).
- Breast cancer (adjuvant/palliative).
- Pancreatic cancer (palliative).
- Esophageal cancer (palliative).
- Topical indications:
- Aphthous ulcers, superficial basal‑cell carcinoma, actinic keratosis, melanoma (in‑situ).
- Combination regimens: FOLFOX, FOLFIRI, CMF, CAPOX, etc.
Contraindications
- Contraindications:
- Known hypersensitivity to fluoropyrimidines.
- Severe hepatic or renal impairment (absorption/clearance concerns).
- Warnings:
- DPD deficiency: Genetic variants (DPYD*2A, *13, c.2846A>G) → life‑threatening toxicity; screen prior to therapy.
- Pregnancy & lactation: Category D; avoid due to teratogenicity.
- Bone marrow suppression: Monitor CBC; risk of severe neutropenia & mucositis.
- Cardiovascular: Rare risk of ischemic events, especially with concurrent cisplatin.
- Precautions:
- Patients with glucose‑6‑phosphate dehydrogenase deficiency may develop hemolysis with high‑dose IV formulations.
Dosing
| Regimen | Dose | Schedule | Notes |
| IV (infusion) | 225–225 mg/m² | 24‑h continuous infusion × 4 days every 2 weeks (FOLFOX) | Pre‑medicated with 5‑HT₃ antagonist. |
| IV (bolus) | 100 mg/m² (4 × 100 mg/m²) | Days 1, 2, 3, 4 every 14 days | Rapid‑dose schedules for acute mucositis. |
| Topical | 5 % gel | Twice daily for 3–10 days | Use occlusive dressing for actinic keratosis. |
| Oral prodrug – Capecitabine | 825 mg/m² BID | 14 days on/7 days off | Equivalent systemic exposure after hepatic activation. |
Adjustments
• Reduce dose by 25 % if DPD deficiency is confirmed.
• Dose modify based on creatinine clearance 10 % N ≥ 3).
Adverse Effects
- Common (≥20 %):
- Myelosuppression (neutropenia, anemia, thrombocytopenia).
- Oral & GI mucositis.
- Diarrhea, nausea, vomiting.
- Hand‑foot skin reaction (HFSR).
- Alopecia.
- Serious (≤5 %):
- Severe infections (neutropenic fever).
- Tumor lysis syndrome (rare in solid tumors).
- Myocardial ischemia, arrhythmias.
- Severe allergic cutaneous reactions.
- Pulmonary fibrosis (rare with prolonged infusion).
Monitoring
- Baseline: CBC, CMP, bilirubin, alkaline phosphatase, creatinine; DPYD genotyping if indicated.
- During therapy (every 2–3 weeks):
- CBC (neutrophils ≥1.5 × 10⁹/L, platelets ≥100 × 10⁹/L).
- Liver function tests (ALT/AST ≤2‑3 × ULN).
- Renal function (creatinine ≤1.5 × ULN).
- Mucositis grading; counsel on oral hygiene.
- Post‑treatment: surveillance imaging per protocol; record late toxicities (e.g., neuropathy, visual changes).
Clinical Pearls
- DPD screening saves lives: A single‑gene test (DPYD *2A *13 — and a panel for common variants) should precede first fluoropyrimidine.
- Infusion schedule matters: 24‑h continuous infusions generate more consistent plasma levels, mitigate peak‑dose toxicity, and enhance DNA damage.
- Topical fluouracil for actinic keratosis: A 5 % gel applied nightly at 30 min before bedtime yields 75 % clearance of lesions after 10 weeks—ideal for patients who cannot tolerate systemic therapy.
- Hand‑foot syndrome early recognition: Warm‑moist compresses and dose adjustments prevent progression; oral 5‑aminosalicylic acid (mesalamine) gels provide relief.
- Capecitabine “cheese” effect: Dietary phospholipids reduce GI toxicity—advise patients to take the drug with a meal high in fats.
- Hematologic toxicity triggers: If neutrophils fall 5 × 10⁹/L, consider dose escalation.
- Drug–drug cautions: Avoid NSAIDs with high CYP2C9 inhibition as they can potentiate fluouracil clearance reduction; always double‑check for concomitant 5‑fluorouracil analogues to prevent additive toxicity.
--
• *This drug card consolidates key pharmacologic, clinical, and safety information for fluorouracil. Clinicians should reference institutional protocols and the latest guidelines (ASCO, NCCN) for updated dosing and monitoring recommendations.*