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Mechanism of Action

Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.

Zileuton is an orally active inhibitor of ex vivo LTB4 formation in several species, including dogs, monkeys, rats, sheep, and rabbits. Zileuton inhibits arachidonic acid-induced ear edema in mice, neutrophil migration in mice in response to polyacrylamide gel, and eosinophil migration into the lungs of antigen-challenged sheep.

Zileuton inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. The compound inhibits leukotriene-dependent bronchospasm in antigen and arachidonic acid-challenged guinea pigs. In antigen-challenged sheep, zileuton inhibits late-phase bronchoconstriction and airway hyperreactivity. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma.


Zileuton is rapidly absorbed upon oral administration with a mean time to peak plasma concentration (Tmax) of 1.7 hours and a mean peak level (Cmax) of 4.98 μg/mL. The absolute bioavailability of ZYFLO is unknown. Systemic exposure (mean AUC) following 600 mg ZYFLO administration is 19.2 μg&bullhr/mL. Plasma concentrations of zileuton are proportional to dose, and steady-state levels are predictable from single-dose pharmacokinetic data. Administration of ZYFLO with food resulted in a small but statistically significant increase (27%) in zileuton Cmax without significant changes in the extent of absorption (AUC) or Tmax. Therefore, ZYFLO can be administered with or without food (see DOSAGE AND ADMINISTRATION).

The apparent volume of distribution (V/F) of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to αl-acid glycoprotein.

Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. Apparent oral clearance of zileuton is 7.0 mL/min/kg. ZYFLO activity is primarily due to the parent drug. Studies with radiolabeled drug demonstrated that orally administered zileuton is well absorbed into the systemic circulation with 94.5% and 2.2% of the radiolabeled dose recovered in urine and feces, respectively. Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric O-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite of zileuton. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose. In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4 (CYP1A2, CYP2C9 and CYP3A4).

Special populations

Effect of age: The pharmacokinetics of zileuton were investigated in healthy elderly volunteers (ages 65 to 81 years, 9 males, 9 females) and healthy young volunteers (ages 20 to 40 years, 5 males and 4 females) after single and multiple oral doses of 600 mg every 6 hours of zileuton. Zileuton pharmacokinetics were similar in healthy elderly subjects ( ≥ 65 years) compared to healthy younger adults (18 to 40 years). Effect of gender: Across several studies, no significant gender effects were observed on the pharmacokinetics of zileuton. Renal insufficiency: The pharmacokinetics of zileuton were similar in healthy subjects and in subjects with mild, moderate, and severe renal insufficiency. In subjects with renal failure requiring hemodialysis, zileuton pharmacokinetics were not altered by hemodialysis and a very small percentage of the administered zileuton dose ( < 0.5%) was removed by hemodialysis. Hence, dosing adjustment in patients with renal dysfunction or undergoing hemodialysis is not necessary. Hepatic insufficiency: ZYFLO is contraindicated in patients with active liver disease (see CONTRAINDICATIONS and PRECAUTIONS, Hepatic).

Clinical Studies

Two double-blind, parallel, placebo-controlled, multi-center studies have established the efficacy of ZYFLO in the treatment of asthma. Three hundred seventy-three (373) patients were enrolled in the 6-month, double-blind phase of Study 1, and 401 patients were enrolled in the 3-month double-blind phase of Study 2. In these studies, the patients were mild-to-moderate asthmatics who had a mean baseline FEV1 of approximately 2.3 liters and who used inhaled beta-agonists as needed, the mean being approximately 6 puffs of albuterol per day from a metered-dose inhaler. In each study, patients were randomized to receive either ZYFLO 400 mg four times daily, ZYFLO 600 mg four times daily, or placebo. Only the ZYFLO 600 mg four times daily dosage regimen was shown to be efficacious by demonstrating statistically significant improvement across several parameters.

Efficacy endpoints measured in Study 1 are shown in Table 1 below as mean change from baseline to the end of the study (six months). Statistically significant differences from placebo at the p < 0.05 level are indicated by an asterisk(*). Similar results were observed after three months in Study 2.


Efficacy Endpoint ZYFLO 600 mg
4 times/day
Trough FEV1 (L) 0.27 0.14
AM PEFR (L/min) 30.60* 5.04
PM PEFR (L/min) 24.59* 7.98
|3-Agonist Use (puffs/day) -1.77* -0.22
Daily Symptom Scorc (0-3 Scale) -0.49* -0.28
Nocturnal Symptom Scorc
(0-3 Scalc) -0.29* -0.04

Figure 1 : shows the mean effect of ZYFLO versus placebo for the primary efficacy variable, trough FEV1, over the course of Study 1.

Figure 1 : Mean Change From Baseline in Trough FEV1 (L)

Mean Change From Baseline in Trough FEV1 - Illustration

Of all the patients in Study 1 and Study 2, 7.0% of those administered ZYFLO 600 mg four times daily required systemic corticosteroid therapy for exacerbation of asthma, whereas 18.7% of the placebo group required corticosteroid treatment. This difference was statistically significant.

In these trials, there was a statistically significant improvement from baseline in FEV1, which occurred 2 hours after initial administration of ZYFLO. This mean increase was approximately 0.10 L greater than that in placebo-treated patients.

These studies evaluated patients receiving as-needed inhaled beta-agonist as their only asthma therapy. In this patient population, post-hoc analyses suggested that individuals with lower FEV1 values at baseline showed a greater improvement.

The role of ZYFLO in the management of patients with more severe asthma, patients receiving anti-asthma therapy other than as-needed, inhaled beta-agonists, or patients receiving it as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.

Last reviewed on RxList: 6/29/2012
This monograph has been modified to include the generic and brand name in many instances.

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