Scientific Article
previous document  unige:10625  next document
add to browser collection
Title

Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist

Authors
Pagliara, Alessandra
Testa, Bernard
Morin, C.
Morin, D.
Urien, S.
Tillement, J. P.
show hidden authors show all authors [1 - 9]
Published in Journal of Medicinal Chemistry. 1998, vol. 41, no. 6, p. 853-863
Abstract The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.
Keywords AlkanesAnimalsBiological TransportBlood Proteins/metabolismBrain/metabolismCetirizine/*chemistry/metabolism/*pharmacokineticsHistamine H1 Antagonists/*chemistry/metabolism/*pharmacokineticsHumansHydrogen BondingHydrogen-Ion ConcentrationHydroxyzine/chemistryIsomerismModels, MolecularMolecular ConformationOctanolsRatsWater
Stable URL http://archive-ouverte.unige.ch/unige:10625
Full text
Article - document accessible for UNIGE members only Limited access to UNIGE
Other version: http://pubs.acs.org/doi/pdf/10.1021/jm9704311
Identifiers
PMID: 9526560
159 hits and 4 downloads since 2010-08-06
Update
Export document
Format :
Citation style :