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.

Pharmacokinetics

Zileuton is rapidly absorbed upon oral administration with a mean time to peak plasma concentration (T_max ) of 1.7 hours and a mean peak level (C_max) of 4.98 µg/mL. The absolute bioavailability of ZYFLO is unknown. Systemic exposure (mean A.C. following 600 mg ZYFLO administration is 19.2 µg.hr/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 C_max without significant changes in the extent of absorption (AUC) or T_max. 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 a_l-acid glycoprotein.

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