Ion-Transfer Voltammetry of Drugs at the Oil|Water Interface and Evaluation of Their Artificial Membrane Permeability By Digital Simulation

Abstract

Prediction of the absorption, distribution, metabolism, and excretion (ADME) of drugs is crucial in the initial step of drug development. For this purpose, quantitative structure–activity relationship (QSAR) studies have been extensively carried out. In the classical QSAR study, Hansch and Fujita claimed that there was a linear free energy relationship (LFER) between the biological activity and the partition coefficient (log⁡ P oct) between 1-octanol and water for compounds. Since then, log⁡ P oct has been extensively used, in QSAR studies, as the scale of hydrophobicity or membrane permeability of compounds. On the other hand, an electrochemical method with the polarized oil|water (O|W) interface as a simple biomembrane model has been used for the study of transfer processes of ionic drugs at the interface. This method, generally called “ion-transfer voltammetry” (ITV), was originated by Gavach et al. in 1968 and its measurement principles were established by Koryta et al. in the latter half of 1970s. Since then, several research groups have used this technique to determine the standard ion-transfer potential (ΔΦ°) for various ionic drugs at the O|W interface, and have found that the values of ΔΦ° gave good correlations with the pharmacological activities. In this study, we employed ITV to study the transfer of protonated or ionized amine drugs (e.g., desipramine, imipramine, labetalol, etc.) at the 1,2-dichloroethane (DCE)|W interface and then determined the ΔΦ° value as well as the distribution coefficient (log⁡ K D) for the neutral form of the amine drugs. It was found that there is a good LFER between the values of ΔΦ° and log⁡ K D that are the hydrophobicity scales of ionic and neutral forms of the amine drugs. However, these hydrophobicity scales did not show a good correlation to log⁡ P oct being conventionally used for QSAR studies. This seems to be due to the difference in the solvation environments of drug molecules in DCE and 1-octanol. The amine drugs studied have either none or different numbers of hydroxyl groups, therefore the amine drugs would be solvated in 1-octanol differently by forming one to three hydrogen bond(s) or not, whereas they form no hydrogen bond in DCE. Such an effect of hydrogen bonds was first suggested by Kontturi and Murtomäki [J. Pharm. Sci., 81, 970 (1992)]. In contrast to log⁡ P oct, the permeability coefficient (log⁡ P pampa) in the widely known parallel artificial membrane permeation assay (PAMPA) showed a clear and characteristic dependence on ΔΦ° (or log⁡ K D). This result suggested that the solvation environment in DCE would be more similar to that in the hydrocarbon region of lipid bilayers than in 1-octanol. Thus, it was shown that ΔΦ°, being easily determined by ion-transfer voltammetry, is a promising scale for predicting drug permeability through lipid membranes. In this study we also developed a digital simulation method for studying the permeation dynamics of drugs in PAMPA. Our method based on the finite-difference method was successfully used to reproduce the experimental dependence of log⁡ P pampa on the hydrophobicity of drug molecules. The leveling-off tendency of log⁡ P pampa for more hydrophobic ions could be explained by the change of the rate-determining step from the diffusion in the membrane to that in the unstirred water layer (UWL) on the donor-solution side of the membrane. It was also suggested that a strongly hydrophobic drug should be significantly retained in the membrane, so that the amount of the drug transported to the acceptor solution is lowered to a great extent. The pH dependence of log⁡ P pampa was also well simulated based on the so-called “pH partition hypothesis”. In conclusion, the developed simulation method is promising for theoretical prediction of the drug permeability across lipid membranes.