Alduet Mechanism of Action

Leukotriene Receptor Antagonist/Antihistamine.
Pharmacology: Pharmacodynamics: Montelukast: The cysteinyl leukotrienes (LTC4, LTD4, and 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.
Cetirizine: Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H1-receptors. In vitro receptor binding studies have shown no measurable affinity for other than H1-receptors.
In addition to its anti-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.
Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.
Pharmacokinetics: Montelukast: Absorption: Montelukast is rapidly absorbed following oral administration. Mean peak plasma concentration (C_max) is achieved 3 hours (T_max) after administration of a 10 mg dose in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion. C_max is achieved in 2 hours after administration of the 5 mg chewable tablet in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. Steady-state volume of distribution of Montelukast averages 8-11 liters. Studies in rats with radio labeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radio labeled material at 24 hours post dose were minimal in all other tissues.
Metabolism: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. 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 radio labeled 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.
Elderly: The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of Montelukast are similar in elderly and younger adults. The plasma half-life of Montelukast is slightly longer in the elderly. Due to the Cetirizine component of Montelukast plus Cetirizine however, dosage adjustment may be required in elderly patients (see Elderly under Dosage & Administration).
Patients with Renal Impairment: Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of Montelukast was not evaluated in patients with renal insufficiency. Due to the Cetirizine component of MONTELUKAST + CETIRIZINE however, dosage adjustment is required in patients with renal impairment (see Patients with Renal Impairment under Dosage & Administration).
Patients with Hepatic Impairment: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Montelukast resulting in 41% (90% CI=7%, 85%) higher mean Montelukast area under the plasma concentration curve (AUC) following a single 10 mg dose. The elimination of Montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of Montelukast in patients with more severe hepatic impairment or with hepatitis has not been evaluated.
Cetirizine: The steady-state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC) is unimodal in human volunteers.
The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.
The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not modify the protein binding of warfarin.
Cetirizine does not undergo extensive first pass metabolism. About two thirds of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.
Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.