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In order to understand and control the therapeutic action of drugs in the human body, one must know how much drug will reach the site(s) of drug action and when this will occur. The absorption, distribution, metabolism (biotransformation), and elimination of drugs are the processes of pharmacokinetics (Figure 2–1). Understanding and employing pharmacokinetic principles can increase the probability of therapeutic success and reduce the occurrence of adverse drug effects in the body.

Figure 2–1.

The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.

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The absorption, distribution, metabolism, excretion, and action of a drug all involve its passage across cell membranes. Mechanisms by which drugs cross membranes and the physicochemical properties of molecules and membranes that influence this transfer are critical to understanding the disposition of drugs in the human body. The characteristics of a drug that predict its movement and availability at sites of action are its molecular size and structural features, degree of ionization, relative lipid solubility of its ionized and non-ionized forms, and its binding to serum and tissue proteins. In most cases, a drug must traverse the plasma membranes of many cells to reach its site of action. Although barriers to drug movement may be a single layer of cells (intestinal epithelium) or several layers of cells and associated extracellular protein (skin), the plasma membrane represents the common barrier to drug distribution.


Cell Membranes. The plasma membrane consists of a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous hydrophobic phase and their hydrophilic heads oriented outward. Individual lipid molecules in the bilayer vary according to the particular membrane and can move laterally and organize themselves with cholesterol (e.g., sphingolipids), endowing the membrane with fluidity, flexibility, organization, high electrical resistance, and relative impermeability to highly polar molecules. Membrane proteins embedded in the bilayer serve as structural anchors, receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways and provide selective targets for drug actions. In contrast to earlier proposals that cell membranes are fluid and thus proteins collide in an unordered fashion, we now understand that membranes are highly ordered and compartmented (Pinaud et al., 2009; Singer, 2004). These proteins may be associated with caveolin and sequestered within caveolae; they may be excluded from caveolae; or they may be organized in signaling domains rich in cholesterol and sphingolipid not containing caveolin or other scaffolding proteins (i.e., lipid rafts).

Cell membranes are relatively permeable to water either by diffusion or by flow resulting from hydrostatic or osmotic differences across the membrane, ...

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