Ionic partition diagram of the zwitterionic antihistamine cetirizine

A recent analysis of the lipophilicity profile of cetirizine in the octanol /water and dodecane/water systems revealed a partial intramolecular charge neutralization that can partly explain why cetirizine has pharmacokinetic p roperties differing from those of first-generation antihistamines such as h ydroxyzine. As conformational changes are the principal driving force for t his intramolecular effect, the present study deals with the partitioning of cetirizine and hydroxyzine in an apolar medium well-suited to reveal intra molecular interactions, namely the 1,2-dichloroethane/water system. The lip ophilicity of the different electrical forms of cetirizine and hydroxyzine was studied by two-phase titrimetry and cyclic voltammetry. The differences in lipophilicity between the dicationic, monocationic, zwitteronic, and an ionic species of cetirizine indicated intramolecular interactions via folde d conformations, which render the molecule markedly more lipophilic than ex pected at physiological pH. Folded conformations were also found to predomi nate in monocationic and neutral hydroxyzine. The ionic partition diagram o f cetirizine indicates that it acts as a proton transporter across interfac es under certain conditions of pH and Galvani potential difference. This st udy underlines the importance of conformational effects on the partition pr operties of cetirizine and hydroxyzine, as well as the complexity of its in terfacial mechanisms of transfer. In particular, cetirizine can facilitate proton transfer, a property of potential biological relevance.