Drug-lipid interactions

Wadkins RM, Houghton PJ (1993) The role of drug-lipid interactions in the biological activity of modulators of multi-drug resistance. Biochim Biophys Acta 1153 225-236... 

Nonmodified silica gel is used most commonly for the separation of substances of medical interest. The separation is based on the interactions (hydrogen bonding, van der Waals forces, and ionic bonding) between the molecules of drugs, lipids, bile acids, etc., and the silica gel. Alumina has similar properties but is rarely used. Successful separation of endogenous substances, drugs, or their metabolites can also be achieved using physically or chemically modified silica gel. 

Dynamic aspects of drugs delivered into lipid bilayer membranes are significant in discussing bioactivities and the mechanism of the drug-membrane interactions. So far, however, the dynamic properties of drugs in the membrane interior have not been well understood. No systematic NMR experiments have been carried out because of the low concentration of the bilayer interior. In this section, we illustrate how to obtain dynamic features of drug molecules trapped in membranes by NMR. 

Kramer, S. D. Jakits-Dieser, C. Wunderli-Allenspach, H., Free fatty acids cause pH-dependent changes in drug-lipid membrane interactions around physiological pH, Pharm. Res. 14, 827-832 (1997). 

Kramer, S. D., Braun, A., Jakits-Deiser, C. and Wunderli-Allenspach, H. (1998). Towards the predictability of drug-lipid membrane interactions the pH-dependent affinity of propranolol to phosphatidylinositol containing liposomes, Pharmaceut. Res., 15, 739-744. 

A further possibility is the formation of liquid crystals on contact with body fluids at the site of application. The initially applied drug solution interacts with body fluids such as plasma, tears, or skin lipids and undergoes a phase transition into a mono-or multiphasic system of liquid crystals (Fig. 15). For example, oily solutions of reverse micellar solutions of phospholipids, which solubilize additional drug, trans-... 

Macromolecules of biological origin perform various functions in the body. For example, proteins which perform the role of biological catalysts in the body are called enzymes, those which are crucial to communication system in the body are called receptors. Carrier proteins carry polar molecules across the cell membrane. Nucleic acids have coded genetic information for the cell. Lipids and carbohydrates are structural parts of the cell membrane. We shall explain the drug-target interaction with the examples of enzymes and receptors. 

The interactions obviously differed between the lipid bilayers and the natural membranes. Furthermore, cholesterol slightly hinders the drug partitioning into the liquid-crystalline bilayers, in agreement with several previous reports, and the drug molecules interact electrostatically with membrane proteins at the hydrophilic interface adjacent to the polar headgroups of the phospholipid molecules (7). 

Kaplun-Frischoff Y, Touitou E. Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids. J Pharm Sci 1997 86 1394-1399. 

Bebawy et al. [186] demonstrated that CPZ (9) and vinblastine inhibited each other s transport in a human lymphoblastic leukemia cell line (CCRF-CEM/VLBioo). CPZ (9) reversed resistance to vinblastine but not to fluores-cently labeled colchicine and it increased resistance to colchicine. Colchicine was supposed to be transported from the inner leaflet of the membrane and vinblastine from the outer leaflet. CPZ (9) was assumed to be located in the inner membrane leaflet where it interacts with anionic groups of phospholipids and it may inhibit vinblastine transport via allosteric interactions. The authors concluded that transport of P-gp substrates and its modulation by CPZ (9) (or verapamil (79)) are dependent on substrate localization inside the membrane. Contrary to CPZ (9) location in the inner leaflet of the membrane, other modulators and substrates of P-gp were proved to be rather localized within the interface region of the membrane. The location of seven P-gp substrates and two modulators within neutral phospholipid bilayers was examined by NMR spectroscopy by Siarheyeva et al. [129]. The substrates and the modulators of P-gp were found in the highest concentrations within the membrane interface region. The role of drug-lipid membrane interactions in MDR and its reversal was reviewed in detail elsewhere [53,187]. 

Sharom FJ. The P-glycoprotein multi drug transporter interactions with membrane lipids, and their modulation of activity. Biochem Soc Trans 1997 25(3) 1088-1096. 

So far the bottleneck in producing protein chips seems to be the preparation of the individual proteins, but for this heavily researched area solutions are on the horizon. The advantage of the protein chip approach is that a comprehensive set of individual proteins can be directly screened in vitro for a wide variety of activity, including protein-drug interactions, protein-lipid interactions, and enzymatic assays using a wide range of in vitro conditions - and faster and cheaper than with conventional methods. 

Artificial membranes are used to study the influence of drug structure and of membrane composition on drug-membrane interactions. Artificial membranes that simulate mammalian membranes can easily be prepared because of the readiness of phospholipids to form lipid bilayers spontaneously. They have a strong tendency to self-associate in water. The macroscopic structure of dispersions of phospholipids depends on the type of lipids and on the water content. The structure and properties of self-assembled phospholipids in excess water have been described [74], and the mechanism of vesicle (synonym for liposome) formation has been reviewed [75]. While the individual components of membranes, proteins and lipids, are made up of atoms and covalent bonds, their association with each other to produce membrane structures is governed largely by hydrophobic effects. The hydrophobic effect is derived from the structure of water and the interaction of other components with the water structure. Because of their enormous hydrogen-bonding capacity, water molecules adopt a structure in both the liquid and solid state. 

---