Chapter 3

The term pharmacokinetics denotes the effects of biologic systems on both endogenous ligands and drugs. Almost all drugs, except those delivered directly to the target tissue where the proposed receptors are located, are absorbed from the site of administration, transported by the circulation to various tissues in the body, and then arrive at the target tissue. At the same time, the body attempts to convert these drugs into forms that allow for easier removal from the body. This sequence represents the absorption, distribution, biotransformation, elimination, and excretion of drugs.

Currently available drugs include inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbohydrates. Drugs may vary in size and molecular weight (MW) from MW 7 for lithium to over MW 50,000 for thrombolytic enzymes. The majority of drugs, however, have molecular weights between 100 and 1,000. They are often found in plants or animals, but many are partially or completely synthetic. Natural drugs, especially herbs, are sometimes thought to be safer than synthesized drugs. This is a popular misconception. The safety of a drug is based on its pharmacodynamic (Chapter 2) and pharmacokinetic properties, not its source.

Aqueous and Lipid Solubility

One of the important properties of a drug is its solubility in various components of the body; for example, the aqueous extracellular and intracellular environments and the lipid membranes of cells. The aqueous solubility of a drug is often a function of the degree of ionization or polarity of the molecule. Water molecules behave as dipoles and are attracted to charged molecules, forming an aqueous shell around them. Conversely, the lipid solubility of a molecule is inversely proportional to its charge. Many drugs are weak bases or weak acids. For such molecules, the pH of the medium determines the fraction of ionized versus nonionized molecules. If the pKa of the drug and the pH of the medium are known, the fraction of molecules in the ionized state can be predicted from the Henderson-Hasselbalch equation (Equation 1):

In Equation 1, “protonated” means associated with a proton; that is, hydrogen ion. This form of the equation applies to both acids and bases. Weak bases are ionized and, therefore, more polar and more water soluble when they are protonated. In contrast, weak acids are not ionized when they are protonated, and so are less water-soluble. The following equations summarize these points for weak bases (Equation 2) and weak acids (Equation 3):

The Henderson-Hasselbalch relationship is clinically important in both the absorption of nutrients and drugs from the gastrointestinal (GI) lumen and excretion of metabolites by the kidneys. In the GI tract, weak acids can be passively absorbed in the stomach where the pH is around 1 to 3 and these acids are nonionized (Figure 3–1a), but weak bases are very poorly absorbed here because they are ionized at ...

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