March 28, 2017
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Zyflo CR

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Zyflo CR


Mechanism of Action

Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB, 4LTC,4 LTD4 and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro and in vivo 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. LTB4, a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC4, LTD4, LTE4) can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF), blood, urine and sputum from asthmatic patients.

Zileuton is an orally active inhibitor of ex vivo LTB4 formation in several species, including mice, rats, rabbits, dogs, sheep, and monkeys. 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. In a mouse model of allergic inflammation, zileuton inhibited neutrophil and eosinophil influx, reduced the levels of multiple cytokines in the BALF, and reduced serum IgE levels. 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. The clinical relevance of these findings is unknown.


Zileuton is an orally active inhibitor of ex vivo LTB4 formation in humans. The inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. In patients with asthma, the IC50 is estimated to be 0.46 µg/mL, and maximum inhibition ≥ 80% is reached at a zileuton concentration of 2 µg/mL. In patients with asthma receiving zileuton immediate-release tablets 600 mg four times daily, peak plasma levels averaging 5.9 µg/mL were associated with a mean LTB4 inhibition of 98%. Zileuton inhibits the synthesis of cysteinyl leukotrienes as demonstrated by reduced urinary LTE4 levels.


Information on the pharmacokinetics of zileuton following the administration of zileuton immediate-release tablets is available in healthy subjects. The results of two clinical pharmacology studies using ZYFLO CR are described below.


A three-way crossover study was conducted in healthy male and female subjects (n=23) with a mean age of 33 (range 20-55) following single dose of 1200 mg (2 x 600 mg) ZYFLO CR tablets under fasted and fed conditions, and two doses of 600 mg zileuton immediate-release tablets every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations (Cmax) and the mean extent of absorption (AUC) of ZYFLO CR by 18 and 34%, respectively, and prolonged Tmax from 2.1 hours to 4.3 hours. The relative bioavailability of ZYFLO CR to zileuton immediate-release tablets with respect to Cmax and AUC under fasted conditions were 0.39 (90% CI: 0.36, 0.43) and 0.57 (90% CI: 0.52, 0.62), respectively. Similarly, relative bioavailability of ZYFLO CR to zileuton immediate-release tablets with respect to Cmax and AUC under fed conditions were 0.45 (90% CI: 0.41, 0.49) and 0.76 (90% CI: 0.70, 0.83), respectively.

A three-way crossover study was conducted in healthy male and female subjects (n=24) with a mean age of 35 (range 19-56) following multiple doses of 1200 mg (2 x 600 mg) ZYFLO CR tablets administered every 12 hours under fasted and fed conditions, and 600 mg zileuton immediate-release tablets every 6 hours under fed conditions until steady state zileuton levels were achieved. Food increased AUC and Cmin of ZYFLO CR by 43% and 170%, respectively, but had no effect on Cmax. Therefore, ZYFLO CR is recommended to be administered with food [see DOSAGE AND ADMINISTRATION]. At steady state, relative bioavailability of ZYFLO CR to zileuton immediate-release tablets with respect to Cmax, Cmin, and AUC were 0.65 (90% CI: 0.60, 0.71), 1.05 (90% CI: 0.88, 1.25) and 0.85 (90% CI: 0.78, 0.92) respectively. These data indicate that at steady state under fed conditions the Cmax of ZYFLO CR is about 35% lower than that of zileuton immediate-release tablets but the Cmin and AUC are similar for both formulations.


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 al-acid glycoprotein.


Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 3.2 hours. Apparent oral clearance (CL/F) of zileuton is 669 mL/min. Zileuton activity is primarily due to the parent drug. Studies with radiolabeled drug have 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.


In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by CYP1A2, CYP2C9 and CYP3A4.

Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric 0-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite (A-66193) of zileuton. The urinary excretion of the inactive A-66193 metabolite and unchanged zileuton each accounted for less than 0.5% of the single radiolabeled dose. Multiple doses of 1200 mg ZYFLO CR twice daily resulted in peak plasma levels of 4.9 µg/mL of the inactive metabolite A-66193 with an AUC of 93 µg-hr/mL, showing large inter-subject variability. This inactive metabolite has been shown to be formed by the gastrointestinal microflora prior to the absorption of zileuton and its formation increases with delayed absorption of zileuton.

Renal Impairment

The pharmacokinetics of zileuton immediate-release tablets 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 Impairment

The pharmacokinetics of zileuton immediate-release tablets were compared between subjects with mild and moderate chronic hepatic insufficiency. The mean apparent plasma clearance of total zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment. ZYFLO CR is contraindicated in patients with active liver disease or persistent ALT elevations ≥ 3xULN [see WARNINGS AND PRECAUTIONS].

Geriatric Use

The pharmacokinetics of zileuton immediate-release tablets were investigated in healthy elderly subjects (ages 65 to 81 years, 9 males, 9 females) and healthy young subjects (ages 20 to 40 years, 5 males, 4 females) after single and multiple oral doses of 600 mg zileuton every 6 hours. Zileuton pharmacokinetics were similar in healthy elderly subjects ( > 65 years) compared to healthy younger adults (20 to 40 years).

Clinical Studies

The efficacy of ZYFLO CR was evaluated in a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial of 12 weeks duration in patients 12 years of age and older with asthma. The 12-week trial included 199 patients randomized to ZYFLO CR (two 600 mg tablets twice daily) and 198 to placebo. Eighty-three percent of patients were white, 48% were male, and the mean age was 34 years. The mean baseline FEV1 percent predicted was 58.5%.

Assessment of efficacy was based upon forced expiratory volume in one second (FEV1) at 12 weeks. ZYFLO CR demonstrated a significantly greater improvement in mean change from baseline trough FEV1 at 12 weeks compared to placebo (0.39 L vs. 0.27 L; p=0.021). The mean change from baseline FEV1 over the course of the 12-week study is shown in Figure 1. Secondary endpoints (PEFR and rescue beta-agonist use) were supportive of efficacy.

Examination of gender subgroups did not identify differences in response between men and women. The database was not large enough to assess whether there were differences in response in age or racial subgroups.

Figure 1. Mean Change from Baseline in Trough FEV1 in 12-Week Clinical Trial in Patients with Asthma.

Mean Change from Baseline in Trough FEV1 - Illustration

Mean Change from Baseline in Trough Forced Expiratory Volume After 1 Second in 12-Week Clinical Trial in Patients With Asthma.
*p ≤ 0.050. Endpoint analysis based on last-observation-carried-forward (LOCF) methodology.

Last reviewed on RxList: 11/29/2016
This monograph has been modified to include the generic and brand name in many instances.

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