After a drug is absorbed systemically from the site of administration, the drug molecules are distributed throughout the body by the systemic circulation. The location, extent, and degree of distribution are dependent on the drug's properties and individual patient characteristics such as organ perfusion and blood flow. The drug molecules are carried by the blood to the target site (receptor) for drug action and to other (nonreceptor) tissues as well, where side effects or adverse reactions may occur. These sites may be intra- and/or extracellular. Drug molecules are distributed to eliminating organs, such as the liver and kidney, and to noneliminating tissues, such as the brain, skin, and muscle. In pregnancy, drugs cross the placenta and may affect the developing fetus. Drugs can also be secreted in milk via the mammillary glands, into the saliva and into other secretory pathways. A substantial portion of the drug may be bound to proteins in the plasma and/or in the tissues. Lipophilic drugs deposit in fat, from which the drug may be slowly released.
Drug distribution throughout the body occurs primarily via the circulatory system, which consists of a series of blood vessels that carry the drug in the blood; these include the arteries that carry blood to tissues, and the veins that return the blood back to the heart. An average subject (70 kg) has about 5 L of blood, which is equivalent to about 3 L of plasma (Fig. 10-1). About 50% of the blood is in the large veins or venous sinuses. The volume of blood pumped by the heart per minute—the cardiac output—is the product of the stroke volume of the heart and the number of heartbeats per minute. An average cardiac output is 0.08 L/left ventricle contraction × 69 contractions (heart beats)/min, or about 5.5 L/min in subjects at rest. The cardiac output may be five to six times higher during exercise. Left ventricular contraction may produce a systolic blood pressure of 120 mm Hg, and moves blood at a linear speed of 300 mm/s through the aorta. Mixing of a drug solution in the blood occurs rapidly at this flow rate. Drug molecules rapidly diffuse through a network of fine capillaries to the tissue spaces filled with interstitial fluid (Fig. 10-2). The interstitial fluid plus the plasma water is termed extracellular water, because these fluids reside outside the cells. Drug molecules may further diffuse from the interstitial fluid across the cell membrane into the cell cytoplasm.
Major water volumes (L) in average 70-kg human.
Diffusion of drug from capillaries to interstitial spaces.
Drug distribution is generally rapid, and most small drug molecules permeate capillary membranes easily. The passage of drug molecules across a cell membrane depends on the physicochemical nature of both the ...