Mechanism Of Action of Montelukast
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products
of arachidonic acid metabolism and are released from various cells, including
mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene
(CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human
airway (including airway smooth muscle cells and airway macrophages) and on
other pro-inflammatory cells (including eosinophils and certain myeloid stem
cells). CysLTs have been correlated with the pathophysiology of asthma and
allergic rhinitis. In asthma, leukotriene-mediated effects include airway
edema, smooth muscle contraction, and altered cellular activity associated with
the inflammatory process. In allergic rhinitis, CysLTs are released from the
nasal mucosa after allergen exposure during both earlyand late-phase reactions
and are associated with symptoms of allergic rhinitis.
Montelukast is an orally active compound that binds with
high affinity and selectivity to the CysLT1 receptor (in preference to other
pharmacologically important airway receptors, such as the prostanoid,
cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic
actions of LTD4 at the CysLT1 receptor without any agonist activity.
Montelukast is more than 99% bound to plasma proteins. The
steady state volume of distribution of montelukast averages 8 to 11 liters. Studies
in rats with radiolabeled montelukast indicate minimal distribution across the
blood-brain barrier. In addition, concentrations of radiolabeled material at 24
hours postdose were minimal in all other tissues.
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