PRINCIPLES OF TOXICOLOGY

42 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTS
have been collected in the nasopharyngeal area and swallowed. Essentially only one cell thick, the
epithelial wall of the GI tract is specialized not only for absorption but also for elimination.
Absorption from the GI tract is strongly site-dependent, since the pH varies from the very acidic
range of about 1–3 in the stomach (depending on the amount and quality of the food and when it was
eaten) to around 5–8 in the small intestine and colon (depending on location, food, and intestinal
microflora). The intestinal contents can therefore be neutral or even slightly basic.
Absorption of Organic Acids and Bases Application of the Henderson-Hasselbalch equation to
organic acids, which have pKa values of 3–5, suggests that they should be relatively well absorbed
from the acidic pH of the stomach. Salicylic acid is shown as an example in Figure 2.4. Its pKa is about
2. The efficiency of its transfer across the gastric mucosa is dependent on the concentration gradient
of the nonionized form across the mucosa as well as on the physical features of salicylic acid that
control its rate of diffusion. As Figure 2.4 shows, in the stomach there are 100 nonionized molecules
of salicylic acid for every salicylate ion. On the plasma side of the mucosal cell, however, there is
relatively little salicylic acid; salicylate ion is overwhelmingly the dominant species. These calculations
were carried out for steady-state conditions. In fact, once salicylic acid molecules have entered the
plasma, they will be both ionized to a large extent and carried away from the absorption site by the
plasma flow. These factors should combine to promote efficient absorption of organic acids from the
stomach. However, organic acids are actually absorbed only moderately well in the stomach, perhaps
because of its relatively small absorbing surface. Organic bases, in contrast, are largely ionized at the
pH of the stomach contents, and so are much more efficiently absorbed from the intestine.
Determinants of GI Absorption A number of other factors are important in determining whether,
and how rapidly, a compound will be absorbed from the GI tract. The physical factors, such as lipid
solubility and molecular size, which determine the rate of diffusion of nonionized species, have already
been discussed. Diffusion is also favored by the presence of villi and microvilli in the intestine. These
greatly increase the surface area available for diffusion. Thus, even though absorption may not be
particularly efficient per unit surface area, the very large total surface area helps to promote intestinal
absorption.
Facilitated and active transport mechanisms present in the GI tract provide specialized transport
for essential nutrients and electrolytes, including sugars, amino acids, sodium, and calcium. A toxicant
that mimics the molecular size, configuration, and charge distribution of an essential nutrient sufficiently
well may be transported by the carrier process already in place for absorption of that nutrient.
Known examples of such mimicry are rare. 5-Fluorouracil has been shown to be absorbed by a
pyrimidine transport mechanism. Interaction among metal ions with respect to their use of common
transport mechanisms has also been documented.
Other factors affect absorption from the GI tract. Compounds that are chemically unstable at the
acid pH of the stomach will not even reach the intestine to be absorbed there. Other compounds are
Figure 2.4 Partitioning of salicylic acid across the gastric mucosa. The numbers in parentheses are the numbers
of molecules of the ionized or nonionized species present on either side of the membrane. (Reproduced with
permission from O’Flaherty, 1981, Figure 2.9.)