Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine
Abstract
Cetirizine, marketed as a racemic mixture containing both levocetirizine and dextrocetirizine, is a member of the second generation H(1) antihistamines clinically used for the treatment of symptoms associated with seasonal allergic rhinitis. Recently, its single R-enantiomer levocetirizine has been approved by the FDA as the newest antihistamine. Cetirizine is a piperazine derivative related to the first generation H(1) antagonist hydroxyzine, and is the major metabolite in the blood circulation after hydroxyzine administration in humans. The acid functionality of cetirizine in combination with one of the basic nitrogens of piperazine ring makes this compound a very unique zwitterion. The molecular structure of cetirizine allows its carboxylic group to interact with the basic nitrogen via folded conformers, therefore, it possesses relatively high lipophilicity at physiological pH (LogD=1.5). While both cetirizine and hydroxyzine possess high affinity at the H(1) receptor, the R-configured levocetirizine has much slower dissociation rate from the H(1) receptor than R-hydroxyzine, making it an insurmountable antagonist. In addition, the pharmacokinetics of cetirizine significantly differs from those of the basic and lipophilic hydroxyzine. For example, cetirizine has much lower CNS penetration than hydroxyzine, which may be explained by the zwitterionic structure of cetirizine and its P-glycoprotein activity. Cetirizine exhibits high intestinal absorption in humans and its…
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