Retention Behavior of Neutral and Positively and Negatively Charged Solutes on an Immobilized‐Artificial‐Membrane (IAM) Stationary Phase

Abstract

The retention behavior of neutral, positively charged, and negatively charged solutes on the IAM.PC.DD2 stationary phase was investigated and compared. A set of monofunctional compounds and complex drugs (steroids, nonsteroidal anti-inflammatory drugs, and b-blockers) were selected for this study, i.e., neutral solutes and solutes with acidic or basic functionalities which are positively charged or negatively charged at pH 7.0. The correlation between the retention factor log k w at pH 7.0 on the IAM.PC.DD2 stationary phase and the partition coefficient log P oct or the distribution coefficient log D 7.0 showed that the retention mechanism depends on the charge state and structural characteristics of the compounds. The neutrals were least retained on the IAM.PC.DD2 stationary phase, and positively charged solutes were more retained than negatively charged ones. This implies that the retention of the charged solutes is controlled not only by lipophilicity but also by the electrostatic interaction with the phospholipid, with which positively charged solutes interact more strongly than negatively charged ones.Introduction. -Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also efficient delivery to that site. Drug design and discovery must take pharmacokinetic behavior into account, in particular absorption and distribution. Numerous quantitative structurepermeability-relationship (QSPR) studies have clearly demonstrated that lipophilicity, as related to membrane partitioning and hence passive transcellular diffusion, is a key parameter in predicting and interpreting permeability [1] [2]. Lipophilicity is generally expressed by the octan-1-ol/H 2 O partition coefficient (log P oct , for a single chemical species) or distribution coefficient (log D oct , for a pH-dependent mixture of ionizable compounds). In some studies, a relationship has been established between log P oct (or log D oct ) and the absorption or permeability in intestinal models [3] [4], blood-brainbarrier models [5], and cell-culture models [6 -9], to name a few. However, in many other situations, log P oct (or log D oct ) cannot give a good estimate of a drugs absorption or permeation [10 -14]. The lipophilicity parameters log P oct or log D oct fail to encode some important recognition forces, most notably ionic bonds, which are of particular importance when modeling the interaction of ionized compounds with biomembranes [15]. Because the majority of the drugs are ionizable [16], any prediction of their pharmacodynamic and pharmacokinetic properties should take their ionization into account.

Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water, and Octan‐1‐ol/Water Systems

“…3, a, shows that b-blockers which are positively charged at the experimental conditions are retained strongest on the ILC column among the three sets of solutes. The same result was also found for IAM chromatography [21]. This suggests that the interaction of ionized drugs with immobilized liposomes depends not only on their lipophilicity expressed as log P oct , but also on additional interactions including electrostatic interactions and their ability to form H-bonds with the polar head groups of the phospholipids (b-blockers can form more H-bonds than alkyl(4-methylbenzyl)-amines).…”

“…It was found that positively charged solutes are more retained than negatively charged solutes on an IAM.PC.DD2 stationary phase [21], which was explained as the result of a larger affinity of positively charged drugs to phospholipid membranes compared to the negatively charged compounds. However, we did not obtain the same results by ILC with immobilized unilamellar egg PC liposomes in this study.…”

“…IAMw values (capacity factor at pH 7.0) were obtained from experiments using an IAM.PC.DD2 HPLC column [21]. The octan-1-ol/H 2 O partitioning data (log P N oct and log D 7:0 oct ) were taken from the literature [21].…”

“…The octan-1-ol/H 2 O partitioning data (log P N oct and log D 7:0 oct ) were taken from the literature [21]. According to the pK a values of the compounds [21], the alkyl(4-methylbenzyl)amines and b-blockers (compounds 1 -14) are fully positively charged, whereas the monofunctional carboxylic acids and NSAIDs (compounds 15 -22) are fully negatively charged at both pH 7.4 and 7.0.…”

Lipophilicity and Its Relationship with Passive Drug Permeation

“…The interaction of drugs with phospholipids has been investigated by IAM-HPLC for different sets of neutral and charged compounds such as β-blockers (90), non-steroidal anti-inflammatory drugs (NSAIDs) (91), dihydropyridine (DHPs) calcium channel blockers (92), and for a set of compounds with a wide structural diversity (93). It was found that log k IAMw values from IAM columns correlate with log P oct only for neutral and structurally related compounds and that electrostatic interactions between the charged solutes and the polar heads of phospholipid play a vital role in IAMs.…”