zileuton
Brand: Zyflo, Zyflo CR
Prototype Drug
Drug Class: 5-lipoxygenase inhibitor
Drug Family: leukotriene modifier
Subclass: leukotriene synthesis inhibitor
Organ Systems: respiratory
Mechanism of Action
Inhibits 5-lipoxygenase, the enzyme that converts arachidonic acid to 5-HPETE and then to all leukotrienes (LTB4, LTC4, LTD4, LTE4); unlike LTRA drugs, zileuton prevents synthesis of all leukotriene subtypes — including LTB4 which promotes neutrophil chemotaxis — providing broader anti-inflammatory activity than receptor antagonists.
5-lipoxygenase (5-LO) enzyme
Indications
- persistent asthma (maintenance therapy, adults and adolescents 12 years and older)
- aspirin-exacerbated respiratory disease
Contraindications
- active hepatic disease
- ALT levels 3 or more times upper limit of normal
- hypersensitivity to zileuton
Adverse Effects
Common
- headache
- nausea
- dyspepsia
- elevated liver enzymes
Serious
- hepatotoxicity (monitoring required)
- neuropsychiatric events (sleep disturbances, irritability — class effect)
- Churg-Strauss syndrome (with steroid tapering)
Pharmacokinetics (ADME)
| Absorption | oral; bioavailability approximately 93%; absorption increased with high-fat meal; controlled-release taken with food |
| Distribution | Vd approximately 1.2 L/kg; 93% protein bound |
| Metabolism | extensive hepatic CYP1A2, CYP2C9, and CYP3A4 metabolism; also inhibits CYP1A2 |
| Excretion | renal (94.5%) |
| Half-life | approximately 2.5 hours (IR); 3-3.5 hours (CR) |
| Onset | days for full effect |
| Peak | 1.7 hours (IR); 4-5 hours (CR) |
| Duration | IR: four times daily; CR: twice daily |
| Protein Binding | 93% |
| Vd | approximately 1.2 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| theophylline | zileuton inhibits CYP1A2; significantly increases theophylline plasma levels — reduce theophylline dose and monitor levels | major |
| warfarin | CYP1A2 and CYP2C9 inhibition increases warfarin exposure; monitor INR | major |
| propranolol | CYP1A2 inhibition doubles propranolol AUC; reduce propranolol dose | major |
Nursing Considerations
- Monitor ALT at baseline, monthly for first 3 months, every 3 months for the rest of the first year, and periodically thereafter; elevations greater than 3 times the ULN require dose interruption and clinical evaluation.
- The 4-times-daily dosing of immediate-release zileuton is a major adherence barrier; the controlled-release formulation (Zyflo CR) reduces dosing to twice daily and is preferred for chronic asthma management.
- Advise patients taking theophylline or warfarin that zileuton significantly inhibits their metabolism; these patients require more frequent monitoring and likely dose reductions when starting zileuton.
- Discuss neuropsychiatric risk with patients and caregivers: insomnia, mood changes, behavioral changes, and suicidal ideation (class effect); instruct them to report new or worsening symptoms promptly.
Clinical Pearls
- Zileuton is the only commercially available 5-lipoxygenase inhibitor; by preventing all leukotriene synthesis rather than just blocking CysLT1 receptors, it may be more effective in aspirin-exacerbated respiratory disease, where LTE4 and LTB4 play prominent roles.
- The combination of high dosing frequency (4 times daily for IR), required hepatic monitoring, and multiple significant drug interactions (theophylline, warfarin, propranolol) makes zileuton the least frequently used controller asthma medication among the options available.
Safety Profile
Pregnancy use-with-caution
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.