| After absorption into the bloodstream, drugs become disseminated to all parts of the body. Compounds that permeate freely through cell membranes become distributed, in time, throughout the body water, both extracellular and intracellular. Substances that pass readily through and between capillary endothelial cells, but do not penetrate other cell membranes, are distributed into the extracellular fluid space. Occasionally, the drug molecule may be so large (>65,000 daltons) or so
highly bound to plasma proteins that it remains in the intravascular space after IV administration. Drugs may also undergo redistribution in the body after initial high levels are achieved in tissues that have a rich vascular supply, eg, the brain. As the plasma concentration falls, the drug readily diffuses back into the circulation to be quickly redistributed to other tissues with high blood-flow rates, such as the muscles; then, over time, the drug also becomes deposited in
lipid-rich tissues with poor blood supplies, such as the fat depots. Most drugs are not distributed equally throughout the body but tend to accumulate in certain specific tissues or fluids. The general principles that govern the passage and distribution of drugs across cellular membranes (see above) are applicable. Basic drugs tend to accumulate in tissues and fluids with pH values lower than the pKa of the drug; conversely, acidic drugs
concentrate in regions of higher pH, provided that the free drug is sufficiently lipid soluble to be able to penetrate the membranes that separate the compartments. Even small differences in pH across boundary membranes, such as those that exist between CSF (pH 7.3) and plasma (pH 7.4), milk (pH 6.5-6.8) and plasma, renal tubular fluid (pH 5.0-8.0) and plasma, and inflamed tissue (pH 6.0-7.0) and healthy tissue (pH 7.0-7.4), can lead to unequal distribution of drugs with
pKa values close to those of the pH of the fluid. Only freely diffusible and unbound drug molecules are able to pass from one compartment to another. Binding to macromolecules such as protein components of cells or fluids, dissolution in adipose tissue, formation of nondiffusible complexes in tissues such as bone, incorporation into specific storage granules, or binding to selective sites in tissues all impede movement of drugs in the body and account for
differences in the cellular and organ distribution of particular drugs. Therapeutic agents may also be transported by carrier-mediated systems across certain cellular membranes, which leads to higher concentrations on one side than the other. Examples of such nonspecific transport mechanisms are found in renal tubular epithelial cells, hepatocytes, and the choroid plexus. |
| Only the unbound or free fraction of a drug can diffuse out of capillaries into tissues. The most important binding of drugs in circulation is to plasma albumin, although the globulins and, especially, α-1 acid glycoprotein (for bases) may also play a significant role. A drug may become bound to plasma proteins to a greater or lesser degree, depending on a number of factors, eg, plasma pH, concentration of plasma proteins, concentration of the drug, the presence of another agent
with a greater affinity for the limited number of binding sites, and the presence of acute-phase proteins during active inflammatory conditions. The degree of plasma-protein binding and the affinity of a drug for the nonspecific protein-binding sites is of great clinical significance in some instances and much less so in others. For example, a potentially toxic compound (such as dicumarol) may be 98% bound, but if for any reason it becomes only 96% bound, then the concentration of
the free active drug that becomes available in the plasma is doubled, with potentially harmful consequences. The concentration of a drug administered in overdose may exceed the binding capacity of the plasma protein and lead to an excess of free drug, which can diffuse into various target tissues and produce exaggerated effects. Of equal importance is the readiness with which drugs dissociate from plasma proteins. Those that are more tightly bound tend to have much longer elimination
half-lives because they are released gradually from the plasma protein reservoir. The long-acting sulfonamides are good examples of this phenomenon. Most unbound drugs distribute easily to extracellular fluid. All membranes are transversed only by the more lipid-soluble drugs. During distribution and elimination from the body, a drug may or may not penetrate certain “physiologic” (eg, blood-brain, placental, and mammary) barriers. A drug may gain access to the CNS by 2 distinct
routes—the capillary circulation and the CSF. Drugs penetrate into the cortex more rapidly than into white matter, probably because of the greater delivery rate of drug via the bloodstream to the tissue. The pharmacologic factors and consequences of the diverse rates of entry of different drugs into the CNS include the following: 1) water-soluble ionized drugs will not enter the CNS; 2) low ionization, low plasma-protein binding, and a fairly high lipid-water partition
coefficient confer ready penetration; 3) direct injections into the CSF often produce unexpected effects; and 4) meningoencephalitis can substantially alter the permeability of the blood-brain barrier. |
| The placental barrier should be considered when selecting an agent to treat a pregnant animal. The potential teratogenicity of any drug needs to be known before its administration; if it is to be used during late gestation, its effects on the fetus and on the process of parturition should be considered. Nutrients, such as glucose, amino acids, minerals, and even some vitamins, are actively transported across the placenta. The passage of drugs across the placenta is largely by lipid
diffusion, and the factors discussed above play a role. The distribution of drugs within the fetus follows essentially the same pattern as in the adult, with some differences with respect to the volumes of drug distribution, plasma-protein binding, blood circulation, and greater permeability of interceding membranous barriers. |
| The mammary gland epithelium, like other biologic membranes, acts as a lipid barrier, and many drugs readily diffuse from the plasma into milk. The pH of milk varies somewhat, but in goats and cows it is generally 6.5-6.8 if mastitis is not present. Weak bases tend to accumulate in milk because the fraction of ionized, nondiffusible drug is higher. The opposite is true for acidic drugs. Agents delivered by intramammary infusion can diffuse into plasma to a greater or lesser degree
by the same processes noted earlier. |
