Experimental modelling of drug membrane permeability by capillary electrophoresis using liposomes, micelles and microemulsions

Abstract

Capillary electrophoresis (CE) was evaluated as an in-vitro format for experimental modelling of membrane permeability using only nanogram quantities of drug compounds. The rationale for the CE technique emanates from emulation of a lipid-like pseudo-stationary phase that governs separations mainly as a result of differences in molecular size, lipophilicity, hydrogen bonding and charge, all of which also have a strong influence on in-vivo drug absorption. By means of micellar, microemulsion and liposome electrolytes, the migration behaviour was studied at 37 degrees C for 22 model drug compounds. The generated CE retention factor data were then compared with membrane permeability reference data. Both simple log D and more common Caco-2 cell parameters were evaluated. In addition, permeation through intestinal segments of rat ileum and rat colon was included. An improved correlation was obtained in the order: micellar < microemulsion < liposome systems. Although the correlation for the best liposome CE system was only R(2)=0.77, the evaluation results for all emphasized the strength and flexibility of CE for assessing specific drug-membrane interaction through tailor-made lipophilic media.

Drug–liposome distribution phenomena studied by capillary electrophoresis‐frontal analysis

“…Also, CE has been used to assess liposomal drug delivery systems in a few cases [18][19][20][21][22]. Liposomes have, however, primarily been introduced into capillaries in studies directed at estimating drug lipophilicity in relation to membrane permeability properties [2][3][4][5][23][24][25][26][27][28]. These studies have been conducted using the liposomes as a pseudostationary phase, i.e., by EKC [2-5, 23-26, 28] or by CEC [27].…”

Recent applications of microemulsion electrokinetic chromatography

“…However, it is important to note that liposome and vesicle systems are in general more difficult to prepare reproducibly and maintain than micellar or microemulsion systems. In addition to the work by Örns-kov et al [49], MEEKC systems have also been shown to be more stable and reliable than MEKC for the estimation of log P, as demonstrated in the pioneering work by Ishihama et al [50], who showed good correlation between the capacity factor (log k 0 ) of MEEKC separations and human skin permeability for acidic nonsteroidal antiinflammatory drugs. Most recently, a comparison between MEEKC and the traditional shake-flask method was carried out by Rappel et al [51] for the estimation of the log P values of a series of promising neutral diamineoxalatoplatinum(II) complexes with highly interesting cyto-toxic and anticancer activity.…”

“…Traditionally, a "gold standard" for the direct determination of log P values of various drug compounds (i.e., characterization of their lipophilicity) is the so-called "shake-flask" technique, but this method is rather laborious, time consuming, and requires relatively large amounts of the pure drugs (mg range). Importantly, indirect methods, such as RP HPLC (immobilized with biomembranes or artificial membranes), as well as electrokinetic chromatographic techniques based on the use of micelles (MEKC), microemulsions (MEEKC), and vesicles/liposomes (VEKC/ LEKC) are becoming attractive alternatives for carrying out log P estimations, since these methods provide experimental data with adequate accuracy and precision, as well as a high degree of automation [47,48].The capabilities of utilizing CE in the mode of MEKC, MEEKC, and LEKC as in vitro methods for the assessment of drug membrane permeability were examined in the recent work of Örnskov et al [49], who compared CE retention factors with membrane permeability reference data (i.e., Caco-2 cell parameters and permeation of drugs through intestinal segments of rat ileum and rat colon). The results indicated that CE using micellar, microemulsions, and liposomes as lipophilic pseudophases are promising experimental approaches for the early assessment of drug membrane permeability, and improved correlation was found to follow the order: MEKC , MEEKC , LEKC.…”

High‐throughput log P determination by MEEKC coupled with UV and MS detections

“…Linear solvation free-energy relationship analyses confirmed that these ME systems were good models for the 1-octanol/water partitioning process [34,37]. Moreover, ME systems mimic more closely phospholipidic membranes than SDS micellar systems [38,39]. Therefore, the MEEKC mode was chosen in this study as it tends to be the most appropriate for log P oct determination.…”