Pharmacology: Pharmacodynamics: Mechanism of action: Levocetirizine, the enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receprtor. Levocetirizine competes with histamine for bindings at H1-receptor sites on the effect or cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The low incidence of sedation can be attributed to reduce penetration of cetirizine into the CNS as a result lipophilic carboxyl group on the ethylamine side chain.
Pharmacokinetics: The pharmacokinetics of levocetirizine are linear with dose- and time-dependent with intersubject 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. In adults, peak plasma concentrations (Cmax) are achieved 0.9 hr after dosing. Steady state is achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. 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, neither concerning the passage of levocetirizine through blood-brain barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the central nervous system (CNS) compartment. 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.
Metabolism: The extent of metabolism of levocetirizine in humans is <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. Dealkylation pathways are primarily mediated by CYP3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5-mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential the interaction of levocetirizine with other substances or vice versa is unlikely.
Elimination: The plasma t½ in adults is 7.9 ± 1.9 hrs. The mean apparent total body clearance in adults is 0.63 mL/min/kg. The major route of excretion of levocetirizine and metabolites is via urine, accounting for the mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.