Drug Absorption

Passage of Drugs Across Cellular Membranes:

Regardless of the route of administration, a drug usually must cross a number of membranes before it reaches its site of action. Membrane barriers may be composed of several layers of cells (eg, skin, vagina, cornea, placenta) or a single layer of cells (eg, enterocytes, renal tubular epithelial cells), or they may consist only of a boundary <1> Drugs and other molecules can cross cellular membranes by several processes. Passive transfer or simple diffusion is the most important for xenobiotics, although specialized transport systems are used for a limited number of therapeutic agents. In simple diffusion, movement of the drug is due to and directly related to its concentration gradient across the membrane. In the case of lipid diffusion, lipid-soluble substances dissolve in the lipid phase of the membrane and diffuse down their concentration gradients into the aqueous phase on the other side of the barrier. Thus, the ability of a compound to cross a membrane by simple lipid diffusion is a function of its degree of lipid solubility (lipid-to-water partition coefficient). The molecular mass of the drug, the thickness of the membrane(s), and the surface area available also influence the rate of diffusion. Many agents of pharmacologic interest are weak organic electrolytes. At physiologic pH, these weak acids or bases may be present partly in the ionized (dissociated) and partly in the nonionized (undissociated) form. The ratio between the respective forms depends on the drug’s dissociation constant (pKa) and the pH of the solution in which it is dissolved. The nonionized fraction may penetrate biologic membranes by lipid diffusion and become distributed across the membrane according to the degree of ionization on each side of the membrane and the extent to which the drug is bound to proteins or other macromolecules in the solutions bathing either side of the membrane. Membranes are more permeable to the undissociated molecule than to the ionized form, simply because the nonionized form is much more lipid soluble. Although a compound may be nonionized, it also may be so poorly soluble in lipids that it penetrates biologic membranes only to a limited extent. A degree of aqueous solubility is also necessary for a drug to be in solution in the body fluids on either side of a cellular membrane. It is supposed that aqueous pores exist in lipoproteinaceous biologic membranes. Lipid-insoluble compounds can easily diffuse through these pores, as well as directly through the membrane, at rates that depend on their molecular masses and concentration gradients. However, with ions or other polar compounds, the speed of transfer is determined by both the charge and molecular dimensions of the drug. When a hydrostatic or osmotic pressure difference exists across a membrane, water flows through the aqueous pores; this bulk fluid movement carries or “drags” solute molecules through the pores in the moving stream, provided that the solute molecules are smaller than the aqueous channels. Several specialized transfer processes account for the passage of certain organic ions and other large lipid-insoluble substances across biologic membranes. Active transport, facilitated diffusion, and exchange diffusion are 3 distinct types of carrier-mediated systems used for moving specific substances across cellular membranes. The highly selective carrier-mediated systems are principally used for transporting nutrients and natural substrates across biologic membranes. Pinocytosis is an important transport process in mammalian cells, particularly intestinal epithelial cells and renal tubular cells. Drugs that exist in solution as molecular aggregates, have large molecular masses themselves, or are bound to macromolecules may be transferred across membranes by pinocytosis.

Drug Absorption from the GI Tract:

Although the basic principles governing the absorption of drugs from the GI tract are understood, many confounding factors may play a role in modifying the process, and erratic responses may result. Some of the more important factors to be considered include the following: 1) molecular size and shape of the drug and its concentration, 2) degree of ionization at specific pH values (depends on pKa of the drug), 3) lipid solubility of the neutral or nonionized form of the drug, 4) chemical or physical interactions with coadministered drug preparations or even food constituents, 5) the pharmaceutical preparation and characteristics of the dosage form (especially the disintegration and dissolution rates of solid dosage forms), 6) morphologic and functional differences of the GI tract among the various animal species, 7) gastric motility, secretion, and the rate of gastric emptying, 8) intestinal motility and secretions as well as the intestinal transit time, 9) fluid volume within the GI tract, 10) osmolality of intestinal content, 11) intestinal blood and lymph flow, 12) disruption of the structural and functional integrity of the gastric and intestinal epithelium, and 13) drug biotransformation within the intestinal lumen by microflora, or within the mucosa by host enzyme systems.

Bioavailability:

This term is used to define the rate and extent to which a drug administered in a particular dosage form enters the systemic circulation intact. All of the considerations outlined above, as well as the particular product used, can influence bioavailability. Biotransformation by intestinal epithelial cells, and particularly by liver cells, can substantially reduce the amount of unchanged drug that enters the systemic circulation after administration PO. This is known as the “first-pass” effect and is significant for a number of drugs.

Drug Absorption from Topical Administration:

Drugs may be absorbed through the skin after topical application; however, the stratum corneum presents an effective barrier to movement of most drugs. The intact skin allows the passage of small lipophilic substances but efficiently retards the diffusion of water-soluble molecules in most cases. Lipid-insoluble drugs generally penetrate the skin slowly in comparison with their rates of absorption through other body membranes. Absorption of drugs through the skin may be enhanced by inunction or more rarely by iontophoresis if the compound is ionized. Certain solvents (eg, dimethyl sulfoxide [DMSO]) may facilitate the penetration of drugs through the skin. Damaged, inflamed, or hyperemic skin allows many drugs to penetrate the dermal barrier much more readily. The same principles that govern the absorption of drugs through the skin also apply to the application of topical preparations on epithelial surfaces.

Drug Absorption from Tracheobronchial Surfaces and Alveoli:

Because volatile and gaseous anesthetics have relatively high lipid-to-water partition coefficients and generally are rather small molecules, they diffuse practically instantaneously into the blood in the alveolar capillaries. Particles contained in aerosols can be deposited, depending on the size of the droplets, on the mucosal surface of the bronchi or bronchioles, or even in the alveoli. Most drugs are usually absorbed quite rapidly from these sites according to the principles discussed above.

Drug Absorption from Parenteral Delivery Sites:

After a drug has penetrated the skin, GI epithelium, or other absorbing surface, or has been deposited by injection into a body tissue, it comes into the immediate vicinity of capillaries. Solutes traverse the capillary wall by a combination of 2 processes: diffusion and filtration. Diffusion is the predominant mode of transfer for lipid-soluble molecules, small lipid-insoluble molecules, and ions. All drugs, whether lipid-soluble or not, cross the capillary wall at rates that are extremely rapid compared with their rates across other body membranes. In fact, the movement of most drug molecules in various tissues is limited only by the rate of blood flow rather than by the capillary wall. However, some endothelial cells, such as the blood-brain barrier, have much tighter intercellular junctions than others and, therefore, restrict drug movement more significantly. Aqueous solutions of drugs are usually absorbed from an IM injection site within 10-30 min, provided blood flow is unimpaired. Faster or slower absorption is possible, depending on the concentration and lipid solubility of the drug, vascularity of the site (there are differences between various muscle groups), the volume of injection, the osmolality of the solution, and other pharmaceutical factors. Substances with molecular weights >20,000 daltons are principally taken up into the lymphatics. Absorption of drugs from subcutaneous tissues is influenced by the same factors that determine the rate of absorption from IM sites. Some drugs are absorbed as rapidly from subcutaneous tissues as from muscle, although absorption from injection sites in subcutaneous fat is always significantly delayed. Increasing blood supply to the injection site by heating, massage, or exercise hastens the rate of dissemination and absorption. Spreading and absorption of a large fluid volume that has been injected SC may be facilitated by including hyaluronidase in the solution. The rate of absorption of an injected drug may be prolonged in a number of ways, including immobilization of the site, local cooling, a tourniquet, incorporation of a vasoconstrictor, an oil base, and implant pellets and other insoluble “depot” preparations. Among these depot preparations are drugs that are converted to less soluble salts (eg, procaine and benzathine penicillin) or less soluble complexes (eg, protamine zinc insulin), or that are administered as insoluble microcrystalline suspensions (eg, methylprednisolone acetate)