Pharmacology Update

Zileuton: A New Asthma Drug

By William T. Elliott, MD, and James Chan, PharmD

The fda has approved zileuton (zyflo, abbott) for the chronic treatment of asthma. Zileuton is an inhibitor of 5-lipoxygenase, the enzyme that catalyzes the production of leukotrienes from arachadonic acid. Zileuton joins zafirlukast (see Intern Med Alert 1996; 18:165-166) as the only commercially available anti-leukotriene drugs. Zileuton differs from zafirlukast in that it is an inhibitor of leukotriene synthesis, while zafirlukast is a leukotriene receptor antagonist.

Leukotrienes mediate a number of components of the pathophysiology of asthma, including bronchoconstriction, airway edema, mucous production, and the recruitment of inflammatory cells.1 Inhibition of leukotrienes helps prevent the onset of wheezing, but these drugs are not useful in acute asthma attacks.


Zileuton is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. It is contraindicated in the presence of acute liver disease. It is not useful for treating acute asthma attacks,2 but it may be continued during an attack.

Potential Advantages

Zileuton provides an oral drug with a different mechanism of action for asthma. When the drug was given to patients with mild-to-moderate asthma (FEV1 40-80%) on inhaled beta-agonists only, a reduction in beta-agonist use was seen (26-31% reduction), as well as a reduction in the use of oral steroids for asthma exacerbation (6-8% vs 16-21% for placebo) and improvement in pulmonary function (FEV1 mean increase of 16%).3,4 In a separate study, zileuton 600 mg qid plus beclomethasone 400 mcg per day was as effective as beclomethasone 800 mcg alone, suggesting that zileuton may be steroid-sparing.5

Potential Disadvantages

Serum ALT should be checked before starting treatment and then monitored monthly for the first three months and every 2-3 months for the remainder of the first year. The overall rate of ALT elevation greater than three times normal or more is 3.2%. Most of these elevations (61%) occurred during the first two months of therapy. Elevated ALTs generally returned to less than two times normal about a month after discontinuation of the drug. Dyspepsia occurs in about 8% of patients.2

Zileuton requires four times a day dosing. However, an unpublished study suggested that patients with baseline FEV1 greater than 75% and responding to zileuton (> 10% increase in FEV1) after qid dosing for two months may be controlled with tid or bid dosing.6 Zileuton interacts with theophylline (doubles theophylline concentration), propranolol (doubles AUC), and terfenadine (increases plasma levels). Zileuton is metabolized by cytochrone P450 1A2, 2C9, and 3A4 isoenzymes.2

Dosing Information

Zileuton is supplied as 600 mg tablets. The drug is given four times a day with or without food. Onset of actions is within 2-4 hours, but peak effects may take weeks to months.2-4


Zileuton is the second leukotriene inhibitor to come on the market. As opposed to zafirlukast, which is a receptor antagonist, zileuton inhibits 5-lipoxygenase, the enzyme that catalyzes production of leukotrienes, thereby inhibiting the formation of a broad range of products including LTB4, LTC4, LTD4, and LTE4. Zafirlukast blocks the receptor for LTD4 and LTE4. LTB4 is believed to be a chemoattractant for leukocytes and involved in inflammatory and immune responses, while LTC4, LTD4, and LTE4 (slow-releasing substances of anaphylaxis) increase vascular permeability, constrict smooth muscle, and increase mucus production.1

In theory, zileuton would produce a more complete inhibition of the leukotriene pathway than zafirlukast, but whether this difference in the mechanisms of action translates into a difference in clinical activity is not known, and there are currently no comparative trials between these agents.

As with zafirlukast, the role of zileuton will be defined with broader clinical experience. In patients with poorly controlled asthma, these agents may be an alternative to increasing the dose of inhaled steroids, theophylline, or salmeterol. However, there are currently no published studies with zileuton in this setting.

Monitoring of liver function for the first year and qid dosing are disadvantages for zileuton, as is the cost of the drug, at $75 per month.

Clinical Implications

The role of leukotriene inhibitors in the treatment of asthma is still unclear. Zileuton seems to be somewhat effective in the prevention of asthma exacerbations and may be steroid-sparing. It has no role in the treatment of acute asthma.


1. Henderson WR. Ann Intern Med 1994;121:684-697.

2. Zyflo Product Information. Abbott, December 1996.

3. Israel F, et al. JAMA 1996;275:931-936.

4. Liu MC, et al. J Allergy Clin Immunol 1996;98:859-871.

5. O’Connor, et al. J Allergy Clin Immunol 1996;97:251.

6. DuBuske LM, et al. Presented at the American College of Allergy, Asthma, and Immunology. November 8-13, 1996.