Leukast Plus Mechanism of Action

Pharmacology: Pharmacodynamics: Pharmacodynamic properties: As Montelukast + Levocetirizine HCl (Leukast Plus) is a combination of Montelukast and Levocetirizine; the pharmacological properties of both the molecules are given separately.
Montelukast: Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics.
Levocetirizine: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki=3.2 nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki=6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min. Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
Pharmacokinetics: Montelukast: Absorption: Mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters.
Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in pediatric patients.
Elimination: Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urines. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%).
Levocetirizine: The pharmacokinetics of levocetirizine are linear with dose and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9h after dosing. Steady state is achieved after two days. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans. Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 L/kg.
Biotransformations: The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O dealkylation and taurine conjugation.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Levocetirizine: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.
Montelukast: In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day >232-fold the systemic exposure seen at the clinical dose. In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day >69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m² and 30,000 mg/m² in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.