Géraldine Bouchard

Lipophilicity and solvation of anionic drugs

This paper first gives a brief review of the main techniques used to measure the lipophilicity of neutral and ionic drugs, namely the shake-flask method, potentiometry, and cyclic voltammetry at liquid-liquid interfaces. The lipophilicity of 28 acidic compounds with various functional groups was studied by potentiometry and cyclic voltammetry in the n-octanol/water and 1,2-dichloroethane/water systems in order to complement our understanding of the lipophilicity of neutral and ionized acids and to clarify the solvation mechanisms responsible for their partition. The parameter diff (log P(N-A)(dce)) (i.e., log P of the neutral acid minus standard log P of the conjugated anion in 1,2-dichloroethane/water) was shown to depend not only on intramolecular interactions and conformational effects in the neutral and anionic forms, but also on the delocalization of the negative charge in the anion, confirming the ability of Borns solvation model to describe qualitatively the effect of the molecular radius on the lipophilicity of ions.

Standard partition coefficients of anionic drugs in the n-octanol/water system determined by voltammetry at three-phase electrodes

The anionic forms of 26 drugs and organic model compounds have been extensively explored in the n-octanol/water system using voltammetry at three-phase electrodes. The objective of this study was to validate the ability of this electrochemical system to give reliable values of lipophilicity for organic ions, as well as to gain more information on the lipophilic behaviour of anions in the n-octanol/water system. Results were used to clarify the solvation mechanisms responsible for ion partitioning and to compare the information obtained in the two solvent systems n-octanol/water and 1,2-dichloroethane/water.

Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB1 cannabinoid receptor ligands and potential antagonists: Synthesis, lipophilicity, affinity, and molecular modeling

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.

Lipophilicity behaviour of the zwitterionic antihistamine cetirizine in phosphatidylcholine liposomes/water systems

AbstractPurpose. The partitioning of cetirizine in a phosphatidylcholine liposomes/water system was compared with that of hydroxyzine and acrivastine to gain insight into the mechanisms of interaction of its various electrical species with membranes. Methods. The lipophilicity profiles of the compounds were obtained from equilibrium dialysis and potentiometry, and compared with changes in NMR relaxation rates. Results. The neutral form of hydroxyzine interacted mainly via hydrophobic interactions with the bilayer lipid core of the membrane, whereas for the cationic form both hydrophobic and electrostatic interactions were involved. Zwitterionic and anionic cetirizine were less lipophilic than its cation, which behaved like the corresponding species of hydroxyzine. Zwitterionic cetirizine interacted more by weak electrostatic interactions with the polar headgroups of phospholipids than by hydrophobic interactions with the membrane interior. The lipophilicity of its anion reflected the balance of repulsive electrostatic interactions between the carboxylate and phosphate groups and the hydrophobic interactions with the lipid core. Conclusion. The study confirms that various mechanisms influence the interaction of solutes with liposomes. Combining experimental techniques and using suitable reference compounds proves useful.

Cyclic voltammetry of highly hydrophilic ions at a supported liquid membrane

Cyclic voltammetry has been used to study the coupling of ion transfer reactions at a liquid membrane. The liquids are either supported by a porous hydrophobic membrane (polyvinylidene difluoride, PVDF) when the organic solvent is non-volatile (o-nitrophenyloctylether) or are merely a free standing organic solvent layer such as 1,2-dichloroethane comprised between two hydrophilic dialysis membranes supporting the adjacent aqueous phases. The passage of current across the liquid membrane is associated with two ion transfer reactions across the two polarised liquid I liquid interfaces in series. It is shown that it is possible to study the transfer of highly hydrophilic ions at one interface by limiting the mass transfer of the other ion transfer reaction at the other interface. Indeed, for systems comprising an ion M in one aqueous phase and a reference ion R partitioned between the membrane and the other aqueous phase, the observed and simulated cyclic voltammograms have a half-wave potential determined by the Gibbs energy of transfer of M transferring at one interface and by the limiting mass transfer of R at the other interface. This new methodology opens a way to measure the Gibbs energy of transfer of highly hydrophilic or hydrophobic ions, which usually limits the potential window at single liquid \ liquid interfaces (ITIES)

Theoretical and Experimental Exploration of the Lipophilicity of Zwitterionic Drugs in the 1,2-Dichloroethane/Water System

AbstractPurpose. This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs. Methods. The lipophilicity of various zwitterionic drugs was examined by potentiometry and cyclic voltammetry in the 1,2-dichloroethane/water system to study the intramolecular interactions and conformational effects affecting absorption and activity of zwitterions, as well as to draw their theoretical and experimental ionic partition diagrams. Results. Different theoretical partition diagrams are reported according to the tautomeric constant of the zwitterion. Shifts of apparent pKa are obtained in the ionic partition diagrams of raclopride and eticlopride and compared to the deviations from pH-absorption profile described in the literature for lipophilic drugs. The physicochemical origin of these shifts is discussed. Conclusions. The comparison between pH-absorption profiles and ionic partition diagrams of zwitterions is shown here to be of value for a better mechanistic understanding of absorption processes, thus opening new perspectives in studying pH-absorption profiles of ionizable drugs.

Water-Oil Partition Profiling of Ionized Drug Molecules Using Cyclic Voltammetry and a 96-Well Microfilter Plate System

AbstractPurpose. A new experimental set-up for studying partitioning of ionizable drugs at the interface between two immiscible electrolyte solutions (ITIES) by amperometry is presented. The method is quite general, as it can be applied to any charged drug molecule. Methods. The procedure is based on 96-well microfilter plates with microporous filters to support 96 organic liquid membranes. The new methodology is first validated using a series of tetra-alkylammonium ions and subsequently used to construct the ion partition diagrams of 3,5-N,N-tetramethylaniline and 2,4-dinitrophenol. The lipophilicity of these drugs was examined by potentiometry and cyclic voltammetry in the NPOE/water system. Results. Cyclic voltammetry resulted in potential-pH profiles of the studied drugs. When the aqueous phase pKa is already known, the logPNPOEof lipophilic drugs could be determined using a very little amount of solvents and drugs. The values of the partition coefficients for the neutral forms agree well with those obtained by potentiometry. Conclusions. The procedure based on commercially available 96-well microfilter plates is shown to be useful for determining logP of ionized drugs in a rapid and efficient way.

The Apparent Lipophilicity of Quaternary Ammonium Ions Is Influenced by Galvani Potential Difference, Not Ion-Pairing: A Cyclic Voltammetry Study

AbstractPurpose. This work examines whether ion–pairing contributes to the apparent lipophilicity of cations, which is seen by a shake–flask or titrimetic method to be influenced by the nature and concentration of counter–ions. Methods. To solve this problem, the lipophilicity of several quaternary ammonium drugs was measured by cyclic voltammetry in the 1,2–dichloroethane/water system. The standard ionic partition coefficient values so obtained (log P°,Cdce) were correlated with log Poct values calculated by the CLOGP algorithm for the respective neutral molecules. Results. The standard (i.e., intrinsic) lipophilicity values are shown to depend on a, the structure of the ion (nature, volume, charge), and b, on the Galvani potential difference at the ITIES (interface between two immiscible electrolyte solutions). Conclusions. The standard lipophilicity values were not influenced by counter–ions. In contrast, simulations showed that the increased apparent lipophilicity of cations, as measured by the shake–flask method in the presence of lipophilic anions, is fully accounted for by the resulting increase in the Galvani potential difference.

Ionic partition diagram of the zwitterionic antihistamine cetirizine

Reference LEPA-ARTICLE-2001-013doi:10.1002/1522-2675(20010228)84:2 3.0.CO;2-4 Record created on 2005-11-07, modified on 2017-05-12

Molecular‐Dynamics and NMR Investigation of the Property Space of the Zwitterionic Antihistamine Cetirizine

The zwitterionic antihistamine cetirizine and its parent drug hydroxyzine as reference compound were examined for their 3D structures and dynamics. After attributing, by NMR spectroscopy, the two basic pK(a) values. the most common conformations for each electrical species were determined by molecular-dynamics simulations and confirmed by NMR measurements. For cetirizine, the results demonstrate that the zwitterion, which is the predominant species at physiological pH, exists as folded conformers able to partly mask polar groups. Extended and folded conformers of similar energy were also found for neutral hydroxyzine. whereas its monocationic species displayed folded conformers stabilized by intramolecular H-bonds. These findings are in lull agreement with previous results on the lipophilicity behavior of cetirizine in isotropic solvent systems and, taken together, could explain the favorable pharmacokinetic properties of the drug