Ionic Partition Diagram of the Zwitterionic Antihistamine Cetirizine

Abstract

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 properties differing from those of first-generation antihistamines such as hydroxyzine. As conformational changes are the principal driving force for this intramolecular effect, the present study deals with the partitioning of cetirizine and hydroxyzine in an apolar medium well-suited to reveal intramolecular interactions, namely the 1,2-dichloroethane/water system. The lipophilicity 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, zwitterionic, and anionic species of cetirizine indicated intramolecular interactions via folded conformations, which render the molecule markedly more lipophilic than expected at physiological pH. Folded conformations were also found to predominate in monocationic and neutral hydroxyzine. The ionic partition diagram of cetirizine indicates that it acts as a proton transporter across interfaces under certain conditions of pH and Galvani potential difference. This study underlines the importance of conformational effects on the partition properties of cetirizine and hydroxyzine, as well as the complexity of its interfacial mechanisms of transfer. In particular, cetirizine can facilitate proton transfer, a property of potential biological relevance.

Use of voltammetry for in vitro equilibrium and transport studies of ionisable drugs

“…Such diagrams are plots of Galvani potential against pH, similar to the Pourbaix diagrams used in corrosion science, and act as a visual representation of which ions predominate, and in which phase, at a given potential and pH. In addition, they give a description of the mechanisms via which the ions transfer between the two phases, be it simple iontransfer, or a proton-coupled transfer, as either potential or pH is varied [19,29].…”

“…As in conventional solid electrode|solution electrochemistry, the current can arise from electron transfer across ITIES and additionally it can also arise from the transfer of ions across ITIES [13][14][15][16][17]. This renders the ITIES ideally suited to the study of ion partitioning across two immiscible phases, which combined with traditional techniques allows for the contribution of ions and neutral compounds to be determined, as shown in the studies of Bouchard et al [18,19], Reymond et al [11], and Nagatani et al [20]. Partition coefficients are simply a measure of solute's affinity for either phase of a liquid|liquid system, as are Gibbs energies of transfer across the ITIES, and therefore the two are directly related.…”

“…An ionic partition diagram for the zwitterionic drug cetirizine, from the study of Bouchard et al [19] is shown in Fig. 3 Ionic-partition diagrams represent the culmination of electrochemical studies of ion-partitioning to this date and provide a valuable first port of call when wishing to understand the partitioning behaviour of an ionised drug under particular conditions of potential and pH.…”

“…In this respect, electrochemical techniques for studying ion partitioning can be viewed as complimentary to traditional techniques, rather than as a replacement for them, and combining the two has resulted in a large expansion in the information which can be gleaned from ion partition studies. [19].…”

Voltammetric study of the partitioning of macrolide antibiotics at the water/nitrobenzene interface. Relationship to the pharmacokinetic profiling of macrolides

“…The interfaces nitrobenzene/water, as well as 1,2-dichloroethane/water are good models for biological membranes, since they enable the rapid and precise determination of the electrochemical properties of ionised biological molecules. Both interfaces have already been used to probe the transfer of ionic drug compounds [14][15][16][17][18].…”