title: Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.
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.
authors.affiliation: Institut de Chimie Thérapeutique, Université de Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Pagliara
authors.forename: B
authors.initials: B
authors.lastname: Testa
authors.forename: P A
authors.initials: PA
authors.lastname: Carrupt
authors.forename: P
authors.initials: P
authors.lastname: Jolliet
authors.forename: C
authors.initials: C
authors.lastname: Morin
authors.forename: D
authors.initials: D
authors.lastname: Morin
authors.forename: S
authors.initials: S
authors.lastname: Urien
authors.forename: J P
authors.initials: JP
authors.lastname: Tillement
authors.forename: J P
authors.initials: JP
authors.lastname: Rihoux
mesh_terms: D000473:Alkanes; D000818:Animals; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D017332:Cetirizine / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D006919:Hydroxyzine / Q000737:chemistry; D007536:Isomerism; D008958:Models, Molecular; D008968:Molecular Conformation; D000442:Octanols; D051381:Rats; D014867:Water
chemical_list: D000473:Alkanes; D001798:Blood Proteins; D006634:Histamine H1 Antagonists; D000442:Octanols; D014867:Water; C007548:n-dodecane; D006919:Hydroxyzine; D017332:Cetirizine