These factors are discussed in more detail below, based on the description of Goodman, et al. (2011, ch. 2). The characteristics of the drug molecule itself that affect the drug’s concentration at the receptor site include its molecular size, degree of ionization, lipid solubility, and its affinity for serum and tissue proteins. The plasma membrane (of skin or intestinal cells, for example) is a common barrier to drug distribution; drugs that are not lipid soluble will not be able to permeate the membrane and not reach the target site. A drug of small molecular size will travel more easily through the membranes than a larger molecule, reaching the target in higher concentrations. Ionized molecules, and those that bind to proteins, also have difficulties in passing through the membrane. If the drug has a tendency to ionize at the pH of the intestinal lumen or the blood, the ionized form will have difficulty passing through lipid plasma membranes. If the drug interacts with transporter proteins on the cell membrane, its uptake into the cell may be increased or decreased, depending on the direction in which the transporter moves the drug. For example, the P-glycoprotein in enterocytes limits the oral absorption of some cancer chemotherapeutic agents by exporting them back into the lumen of the GI tract. Similarly, it has been found that multidrug transporters such as P-glycoprotein (PGP) and members of the multidrug resistance-associated protein (MRP) family are over-expressed in capillary endothelial cells in epileptogenic brain tissue, and, by transporting anti-epileptic drugs out, these proteins may be responsible for the pharmacoresistance of the epileptic brain to anti-epileptic drugs (Löscher and Potschka, 2002).
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