Drug permeation proceeds by several mechanisms. Passive diffusion in an aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily (Figure 1–4). Drug vehicles can be very important in facilitating transport and permeation, eg, by encapsulating the active agent in liposomes and in regulating release, as in slow release preparations. Newer methods of facilitating transport of drugs by coupling them to nanoparticles are under investigation.
1. Aqueous diffusion—Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000. * See Figure 1–4A.
* The capillaries of the brain, the testes, and some other tissues arecharacterized by the absence of pores that permit aqueous diffusion.They may also contain high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore protected or“sanctuary” sites from many circulating drugs.
FIGURE 1–4 Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then be released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).
Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick’s law (see below). Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and— in parts of the nephron—the transtubular potential).
2.
Lipid diffusion—Lipid diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation (described in the following text). See Figure 1–4B.
3.
Special carriers—Special carrier molecules exist for many substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, and glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are selective, saturable, and inhibitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes. See Figure 1–4C.