PRINCIPLES OF TOXICOLOGY - Biology East Borneo

42 ABSORPTION, DISTRIBUTION, AND ELIMINATION OF TOXIC AGENTShave been collected in the nasopharyngeal area and swallowed. Essentially only one cell thick, theepithelial 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 acidicrange of about 1–3 in the stomach (depending on the amount and quality of the food and when it waseaten) to around 5–8 in the small intestine and colon (depending on location, food, and intestinalmicroflora). The intestinal contents can therefore be neutral or even slightly basic.Absorption of Organic Acids and Bases Application of the Henderson-Hasselbalch equation toorganic acids, which have pK a values of 3–5, suggests that they should be relatively well absorbedfrom the acidic pH of the stomach. Salicylic acid is shown as an example in Figure 2.4. Its pK a is about2. The efficiency of its transfer across the gastric mucosa is dependent on the concentration gradientof the nonionized form across the mucosa as well as on the physical features of salicylic acid thatcontrol its rate of diffusion. As Figure 2.4 shows, in the stomach there are 100 nonionized moleculesof salicylic acid for every salicylate ion. On the plasma side of the mucosal cell, however, there isrelatively little salicylic acid; salicylate ion is overwhelmingly the dominant species. These calculationswere carried out for steady-state conditions. In fact, once salicylic acid molecules have entered theplasma, they will be both ionized to a large extent and carried away from the absorption site by theplasma flow. These factors should combine to promote efficient absorption of organic acids from thestomach. However, organic acids are actually absorbed only moderately well in the stomach, perhapsbecause of its relatively small absorbing surface. Organic bases, in contrast, are largely ionized at thepH 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 lipidsolubility and molecular size, which determine the rate of diffusion of nonionized species, have alreadybeen discussed. Diffusion is also favored by the presence of villi and microvilli in the intestine. Thesegreatly increase the surface area available for diffusion. Thus, even though absorption may not beparticularly efficient per unit surface area, the very large total surface area helps to promote intestinalabsorption.Facilitated and active transport mechanisms present in the GI tract provide specialized transportfor essential nutrients and electrolytes, including sugars, amino acids, sodium, and calcium. A toxicantthat mimics the molecular size, configuration, and charge distribution of an essential nutrient sufficientlywell 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 apyrimidine transport mechanism. Interaction among metal ions with respect to their use of commontransport mechanisms has also been documented.Other factors affect absorption from the GI tract. Compounds that are chemically unstable at theacid pH of the stomach will not even reach the intestine to be absorbed there. Other compounds areFigure 2.4 Partitioning of salicylic acid across the gastric mucosa. The numbers in parentheses are the numbersof molecules of the ionized or nonionized species present on either side of the membrane. (Reproduced withpermission from O’Flaherty, 1981, Figure 2.9.)