Pharmacology: The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators 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 bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor.
Pharmacokinetics: Absorption: Montelukast is rapidly absorbed following oral administration. For the 10-mg film coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8-11 liters.
Biotransformation: Montelukast is extensively metabolized. The contribution of metabolites to the therapeutic effect of Montelukast is minimal.
Elimination: The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and < 0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates that Montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in Patients: No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because Montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of Montelukast in patients with severe hepatic insufficiency (Child-Pugh score > 9).
With high doses of Montelukast (20- and 60-fold the recommended adult dose), decrease in plasma Theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.