Pharmacokinetic Principles

Pharmacokinetic Principles

A drug should be able to reach its intended site of action after administration by some convenient route. In some cases, a chemical that is readily absorbed and distributed is administered and then converted to an active drug by biologic processes—inside the body. Such a chemical is called a prodrug. In only a few situations is it possible to directly apply a drug to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or
mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain. This requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that separate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that comprise the wall of the intestine, the walls of the capillaries that perfuse the gut, and the “blood-brain barrier,” the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a
drug should be eliminated at a reasonable rate by metabolic inactivation, excretion from the body, or by a combination of these processes.

Drug permeation proceeds by four primary 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.

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* .

* The capillaries of the brain, the testes, and some other tissues are characterized by absence of the pores that permit the aqueous diffusion of many drug molecules into the tissue. 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.

Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick’s law. Drug molecules that are bound to large plasma proteins (eg, albumin) will not permeate these 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 trans tubular potential).

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.

Special Carriers

Special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipids to diffuse passively through membranes, eg, peptides, amino acids, and glucose. These carriers bring about the movement by active transport or facilitated diffusion and, unlike passive diffusion, are saturable and inhabitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes.

Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules, eg, the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in the brain, testes, and other tissues, and in some drug-resistant neoplastic cells. A similar transport molecule, the multidrug resistance-associated protein-type 2 (MRP2) transporter, plays an important role in the excretion of some drugs or their metabolites into urine and bile.

Endocytosis and Exocytosis

A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by the breakdown of the vesicle membrane. This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor), across the wall of the gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins
must be present for this process to work. The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes the fusion of the storage vesicle with the cell membrane and the expulsion of its contents into the extracellular space.

Fick’s Law of Diffusion
The passive flux of molecules down a concentration gradient is given by Fick’s law:

Pharmacokinetic Principles



where C1 is the higher concentration, C2 is the lower concentration, and the area is the area across which diffusion is occurring, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the thickness (length) of the diffusion path. In the case of lipid diffusion, the lipid: aqueous partition coefficient is a major determinant of the mobility of the drug, since it determines how readily the drug enters the lipid membrane from the aqueous medium.

Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation

The electrostatic charge of an ionized molecule attracts water dipoles and results in a polar, relatively water-soluble, and lipid-insoluble complex. Since lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes.
A very large fraction of the drugs in use are weak acids or weak bases. For drugs, a weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion (negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin dissociates as follows:

Pharmacokinetic Principles




Reference: Bertram Katzung – Basic & Clinical Pharmacology.