Although some substances are translocated by specialized transport mechanisms and small polar compounds may filter through membrane pores, most foreign compounds penetrate cells by diffusing through lipid membranes. A model of membrane structure, shown in Figure 3.2, envisions the membrane as a mosaic structure composed of a discontinuous bimolecular lipid layer with fluidlike properties. A smaller component consists of glycoproteins or lipoproteins that are embedded in the lipid matrix and have ionic and polar groups protruding from one or both sides of the membrane. This membrane is thought to be capable of undergoing rapid local shifts, whereby the relative geome try of specific adjacent proteins may change to form channels, or pores. The pores permit the membrane to be less restrictive to the passage of low-molecular-weight hydrophilic substances into cells. In addition to its role as a barrier to solutes, the cell membrane has an important function in providing a structural matrix for a variety of enzymes and drug receptors. The model depicted is not thought to apply to capillaries.
Physicochemical Properties of Drugs and the Influence of pH
The ability of a drug to diffuse across membranes is frequently expressed in terms of its lipid-water partition coefficient rather than its lipid solubility per se. This coefficient is defined as the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (frequently octanol), representing the membrane; and an aqueous buffer, usually at pH 7.4, representing the plasma. The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. Increasing the polarity of a drug, either by increasing its degree of ionization or by adding a carboxyl, hydroxyl, or amino group to the molecule, decreases the lipid-water partition coefficient. Alternatively, reducing drug polarity through suppression of ionization or adding lipophilic (e.g., phenyl or t-butyl) groups results in an increase in the lipid-water partition coefficient.
Drugs, like most organic electrolytes, generally do not completely dissociate (i.e., form ions) in aqueous solution. Only a certain proportion of an organic drug molecule will ionize at a given pH. The smaller the fraction of total drug molecules ionized, the weaker the electrolyte. Since most drugs are either weak organic acids or bases (i.e., weak electrolytes), their degree of
Drug Administration (e.g., parenteral, oral, etc.)
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