Zileuton
Zileuton
Generic Name
Zileuton
Mechanism
- Selective 5‑lipoxygenase inhibitor – blocks the conversion of arachidonic acid to leukotriene A₄.
- ↓ Production of cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) and leukotriene B₄ (LTB₄).
- ↓ Leukotriene‑mediated bronchoconstriction, eosinophil recruitment, mucous secretion, and airway hyperresponsiveness.
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Pharmacokinetics
| Parameter | Typical Value (adult) |
| Absorption | Rapid; *Cₘₐₓ* ~ 1–2 h after dosing. Enhanced 5‑fold by ingestion with a high‑fat meal. |
| Bioavailability | 10–20 % (very low) – increases up to 50 % when taken with food. |
| Distribution | Extensive; plasma protein binding 96 %. |
| Metabolism | Hepatic, mainly CYP3A4‑mediated oxidative metabolism. |
| Elimination | 50–60 % renal (urine), 30–40 % biliary. Clearance ~ 15–20 L/h. |
| Half‑life | 2–3 h (rapid due to high first‑pass extraction). |
| Drug interactions | Strong CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) ↑ plasma levels → hepatotoxicity risk. CYP3A4 inducers (rifampin, carbamazepine) ↓ efficacy. |
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Indications
- Long‑term maintenance therapy for mild‑to‑moderate asthma in adults and adolescents ≥ 6 years.
- May be used as add‑on therapy when inhaled corticosteroids (ICS) alone are insufficient and to reduce oral steroid exposure.
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Contraindications
| Category | Detail |
| Contraindications | Severe hepatic impairment; known hypersensitivity to zileuton. |
| Warnings | Hepatotoxicity (↑ AST/ALT, jaundice); pancreatitis; bone marrow suppression; potential QT prolongation with concomitant drugs. |
| Precautions |
• Alcohol consumption may increase hepatotoxic risk. • Use cautiously in pregnancy (Category C) and lactation. • Monitor patients with chronic liver disease or concurrent hepatotoxic drugs. |
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Dosing
| Population | Dose | Schedule | Special Notes |
| Adults & adolescents (≥ 6 yrs) | 600 mg PO BID | Taken with meals to enhance absorption | Alternate 800 mg BID if sub‑optimal control but monitor LFTs. |
| Pediatrics ≥ 6 yrs, ≤ 60 kg | 8 mg/kg/day (max 600 mg BID) | Same as adults | Weight‑based initial dose; switch to fixed dose once stable. |
| Storage | Store at 15–30 °C; protect from moisture. | – | – |
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Adverse Effects
Common (≤ 5 % incidence)
• Nausea, vomiting, and indigestion
• Headache and dizziness
• Pruritus, rash
• Sore throat
Serious (≤ 0.5 % incidence)
• Hepatotoxicity – ↑ ALT/AST, icteric rash, liver failure.
• Pancreatitis – epigastric pain, amylase/lipase rise.
• Bone marrow suppression – leukopenia, thrombocytopenia.
• QT interval prolongation (rare) – treat with caution if co‑administered with QT‑prolonging drugs.
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Monitoring
| Parameter | Timing | Rationale |
| Baseline LFTs (ALT/AST, bilirubin) | Pre‑initiation | Identify pre‑existing liver disease. |
| LFTs | 2 weeks, 4 weeks, 8 weeks, then monthly for 6 mo** | Detect hepatotoxicity early. |
| CBC | Baseline, 4 weeks, then every 3 mo** | Monitor for bone marrow suppression. |
| Serum amylase/lipase | If abdominal pain develops | Rule out pancreatitis. |
| Pulmonary function tests (FEV₁) | Every 3 mo** | Evaluate asthma control. |
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Clinical Pearls
1. Food matters – Take with a high‑fat meal; this increases plasma concentration by ~5‑fold, which is essential for therapeutic effect.
2. Liver safety first – Discontinue immediately if ALT/AST > 3 × ULN or any clinical signs of hepatic injury.
3. Medication check – Avoid concomitant strong CYP3A4 inhibitors; if unavoidable, reduce dose and monitor LFTs closely.
4. Adopt it wisely – Best suited for patients who cannot tolerate inhaled steroids long‑term or those who need steroid sparing to reduce systemic side effects.
5. Pediatric dosing nuance – Use weight‑based 8 mg/kg/day in children ≤ 60 kg, but once weight exceeds 75 kg, switch to 600 mg BID to simplify therapy.
6. Rare but notable – Report any episodes of rash, jaundice, or unexplained fever promptly; early hepatotoxicity can be reversible if caught early.
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