Figure 9.1 (a) Cell membranes are composed primarily of phospholipid amphiphiles. (b) Cholesterol molecules act as rigidifiers which make the membrane stiffer. Three representations of cholesterol are shown: a space-filling molecule (top right), a structural diagram (bottom) and a simplified block diagram (top left).

Source: http://physioweb.med.uum.edu.

Figure 9.2 Representation of the 'fluid mosaic' model of a biological membrane, showing embedded protein and protruding glycoproteins. From Funhouse Films.

Although most of the data on permeation of nonelectrolytes across biological membranes can be explained on the basis of the membrane behaving as a continuous hydrophobic phase, a fraction of the membrane may be composed of aqueous channels which are continuous across the membrane. That is, there are pores which offer a pathway parallel to the diffusion pathway through the lipid. In the absence of bulk flow (that is flow of water in one direction or the other (see below)) these pores play a minor part in the transfer of drugs, although in the case of ions and charged drugs such as the quaternary ammonium compounds the pore pathway must be important. The low electrical resistance of membranes compared with synthetic lipid membranes suggests that the ions move in the pores. These pores may be provided by the conjunction of hydrophilic faces of proteins or the polar heads of fatty acids and phospholipids orientated in the appropriate direction. The fluid mosaic model, in particular, allows the protein-lipid complexes to form either hydrophilic or hydrophobic 'gates' to allow transport of materials with different characteristics.

It has been suggested that the permeability of the lipid bilayer is regulated by the density of hydrogen bonding in the outer polar layers of the membranes which contain the phosphate, ammonium and carboxyl head groups of phospholipids and the hydroxyl groups of cholesterol. Overall, membrane permeability is controlled by the nature of the membrane, its degree of internal bonding and rigidity, its surface charge and the nature of the solute being transported.

There are some similarities between solute transport in biological membranes and in synthetic membranes. As we have discussed in Chapter 8, the permeation of drugs and other molecules through hydrophobic membranes made of polydimethylsiloxane, for example, depends primarily on the solubility of the drug in the membrane. Drugs with little affinity for the membrane are unlikely to permeate, although in porous membranes, such as those of cellophane or collagen, even drugs with little affinity for the polymer may be transported through the pores.

Most biological membranes bear a surface negative charge, so one would imagine that this might influence permeation. Membranes with unionized surfaces (such as cellophane) or positively charged surfaces such as collagen have different permeability characteristics for ionic drugs. Indeed, molecular forms of solutes permeate faster than ionic forms through membranes composed of collagen, which have been used as potential haemodialysis membranes or release-controlling membranes for medication of the eye. Crucially, anionic solutes permeate faster than cationic solutes. With amphoteric drugs such as sulfasomidine and sulfamethizole, a similar order of permeation may be observed depending on the pH of the medium, namely: unionised > anionic > cationic form. The most likely explanation is that the basic groups in collagen, which are mainly the basic amino acids lysine, arginine and histidine, are positively charged, as the pKa of lysine and of arginine is about 10. In acidic media the membrane is positively charged and cationic drugs will therefore be repelled from the surface.

pH has little effect on the passage of drugs through cellophane membranes, a fact that can be rationalised by the lack of charge on the cellophane surface. In biological membranes, one might expect some preference for cationic drugs, other things being equal, but we have to remember that biological membranes are more complex and more dynamic than synthetic membranes and there are many confounding factors. One of these, which is outside the scope of this book, is the existence of efflux mechanisms centred on P-glycoproteins (Pgp). Some drugs are ejected from cells by the efflux pump, so that these drugs have a lower apparent absorption than predicted on physicochemical grounds.

In Chapter 5 we examined some relationships between the lipophilicity of drugs and their activity, which was usually controlled by their ability to pass across lipid membranes and barriers. Although of the same basic con struction, biological membranes in different sites in the body serve different functions and thus one might expect them to have different compositions and physicochemical properties, as indeed they do. Tissues derived from the ectoderm (the epidermis, the epithelium of nose and mouth and the anus, and the tissues of the nervous system) have protective and sensory functions. Tissues evolved from the endoderm, such as the epithelium of the gastrointestinal tract, have evolved mainly to allow absorption.

9.1.1 Lipophilicity and absorption

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