These membranes are biologic barriers that selectively inhibit the passage of drug molecules and are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids. The lipids provide stability to the membrane and determine its permeability characteristics. Drugs may cross a biologic barrier by passive diffusion, facilitated passive diffusion, active transport, or pinocytosis. Because drug molecules are rapidly removed by the systemic circulation and distributed into a large volume of body fluids and tissues, drug concentration in blood is initially low compared with that at the administration site, producing a large gradient. The diffusion rate is directly proportional to the gradient but also depends on the molecule's lipid solubility, degree of ionization, and size and on the area of the absorptive surface.
Small molecules tend to penetrate membranes more rapidly than large ones.
Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an aqueous environment. The un-ionized form is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility and high electrical resistance, resulting from its charge and the charged groups on the cell membrane surface. Thus, drug penetration may be attributed mostly to the un-ionized form. For a weak acid, the higher the pH, the lower the ratio of un-ionized to ionized forms.