Zileuton

Zileuton is a medication that helps manage asthma by inhibiting 5-lipoxygenase, an enzyme responsible for producing leukotrienes. These chemicals contribute to airway inflammation, constriction, and mucus buildup, worsening asthma symptoms. By blocking 5-lipoxygenase, Zileuton reduces inflammation and improves lung function. The U.S. FDA approved Zileuton in 1996 for treating asthma in individuals aged 12 and older. It is also approved for asthma treatment in other countries.

BRAND NAMES

Zyflo: Zyflo, which contains the active ingredient zileuton, is a leukotriene synthesis inhibitor used to manage chronic asthma and reduce asthma attacks. It is available as extended-release tablets, each containing 600mg of zileuton.

MECHANISM OF ACTION

Zileuton is a 5-lipoxygenase inhibitor that blocks the formation of leukotrienes B4, C4, D4, and E4. By limiting these leukotrienes, it helps reduce inflammation, edema, mucus secretion, and bronchoconstriction in the airways. This action decreases leukocyte adhesion, smooth muscle contraction, capillary permeability, and the migration and aggregation of neutrophils and eosinophil’s, leading to fewer asthma exacerbations and improved asthma symptoms.

PHARMACOKINETICS

Absorption: Zileuton is quickly absorbed after oral administration, with peak plasma concentration reached in about 1.7 hours.

Distribution: Zileuton has an apparent volume of distribution of approximately 1.2 L/kg and is highly protein-bound (93%), primarily to albumin, with a small portion bound to α-1-acid glycoprotein.

Metabolism: Zileuton is mainly metabolized in the liver by the cytochrome P450 system, including CYP1A2, CYP2C9, and CYP3A4. Its significant metabolites include 2 glucuronide conjugates and an N-dehydroxylated metabolite. The pharmacological activity is primarily due to the parent drug.

Elimination: Zileuton and its metabolites are mostly excreted through urine (94.5%). The average terminal half-life of zileuton is 2.5 hours.

DOSAGE AND ADMINISTRATION

• Adult dosage: The typical recommended dose for adults is 600 mg taken orally four times a day.
• Pediatric dosage: For children aged 12 years and older, the usual dosage is the same as for adults: 600 mg four times daily.
• Administration: Zileuton should be taken with or without food. It is important to follow the prescribed dosing schedule to maintain consistent levels of the drug in the system.
• Renal and Hepatic Impairment: Adjustments may be necessary for patients with liver issues since zileuton is metabolized in the liver. Patients with moderate to severe liver impairment should not use zileuton.

DRUG INTERACTIONS

• CYP450 Inhibitors (e.g., fluconazole) may increase zileuton levels.
• CYP450 Inducers (e.g., rifampin) may decrease zileuton effectiveness.
• Warfarin: Zileuton can enhance its anticoagulant effect.
• Theophylline: Zileuton may increase theophylline levels, raising toxicity risk.

CONTRAINDICATIONS

• Liver Disease: Zileuton is contraindicated in patients with active liver disease or persistent liver dysfunction due to its potential impact on liver function.
• Hypersensitivity: It should not be used in individuals with a known allergy to zileuton or any of its components.

SIDE EFFECTS

Common side effects of Zileuton include:

• Headaches
• Gastrointestinal symptoms (such as nausea, diarrhea, and abdominal discomfort)
• Drowsiness or dizziness

Serious side effects may include:

• Liver issues (elevated liver enzymes, liver inflammation)
• Allergic reactions (such as rash, itching, and swelling)
• Mood changes (including depression or irritability)

TOXICITY

Liver toxicity is the primary risk, with potential for elevated liver enzymes or hepatitis. Regular liver monitoring is required. Overdose symptoms may include drowsiness and gastrointestinal issues.