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Figure 17 (A) Demeclocycline serum concentrations as a function of time in four to six subjects after oral ingestion of demeclocycline in the absence or presence of dairy meals. Key: 1, meal (no dairy products); 2, water; 3, 110 g cottage cheese; 4, 240 mL buttermilk; 5, 240 mL whole milk. (B) Tetracycline serum concentrations as a function of time in six subjects after oral ingestion of tetracycline in the absence or presence of iron salts (equivalent to 40 mg elemental iron). Key: 1, control; 2, ferrous gluconate; 3, ferrous sulfate. Source: Part A based on data from Ref. 122 and part B based on data from Ref. 123.

Figure 17 (A) Demeclocycline serum concentrations as a function of time in four to six subjects after oral ingestion of demeclocycline in the absence or presence of dairy meals. Key: 1, meal (no dairy products); 2, water; 3, 110 g cottage cheese; 4, 240 mL buttermilk; 5, 240 mL whole milk. (B) Tetracycline serum concentrations as a function of time in six subjects after oral ingestion of tetracycline in the absence or presence of iron salts (equivalent to 40 mg elemental iron). Key: 1, control; 2, ferrous gluconate; 3, ferrous sulfate. Source: Part A based on data from Ref. 122 and part B based on data from Ref. 123.

gastric fluids and for dosage forms designed to release drug slowly. Food provides a rather viscous environment that will reduce the rate of drug dissolution and drug diffusion to the absorbing membrane. Drugs may also bind to food particles or react with GI fluids secreted in response to the presence of food.

The absorption of tetracycline is reduced by calcium salts present in dairy foods and by several other cations, including magnesium and aluminum (120-122), which are often present in antacid preparations. In addition, iron and zinc have been shown to reduce tetracycline absorption (123). Figure 17 illustrates several of these interactions. These cations react with tetracycline to form a water-insoluble and nonabsorbable complex. Obviously, these offending materials should not be coadministered with tetracycline antibiotics. Heavy metals, in general, may create this type of problem, and it is a good precaution to separate in time the administration of those metals from drug ingestion.

The tetracycline example cited above is one type of physical-chemical interaction that may alter absorption. The relative influence of complexation on drug absorption will depend on the water solubility of the drug, the water solubility of the complex, and the magnitude of the interaction (i.e., the complexation stability constant). If the drug itself is poorly water soluble, the absorption pattern will be governed by rate of dissolution. Often such compounds are incompletely and erratically absorbed. As a result, complexation will probably exert more of an influence on the absorption of such a compound than on one that is normally well absorbed, although this will depend on the nature of the complex. If the complex is water insoluble, as in the case of tetracycline interactions with various metal cations, the fraction complexed will be unavailable for absorption. Although most complexation interactions are reversible, the greater the stability constant of the complex, the greater the relative influence on absorption. Generally, however, because the interaction is reversible, complexation is more likely to influence the rate rather than the extent of absorption.

Surface-active agents, because they are able to form micelles above the critical micelle concentration, may bind drugs either by inclusion within the micelle (solubilization) or by attachment to its surface. Below the critical micelle concentration, surfactant monomers have a membrane-disrupting effect, which can enhance drug penetration across a membrane. The latter influence has been seen in drug absorption studies in animals. The influence of surface-active agents on drug absorption will depend on the surfactant concentration and the physicochemical characteristics of the drug. If the drug is capable of partitioning from the aqueous to the micellar phase, and if the micelle is not absorbed, which is usually the case, there may be a reduction in rate of absorption. Micellar concentrations of sodium lauryl sulfate or polysorbate 80 (Tween 80) increase the rectal absorption rate of potassium iodide in the rat but reduce the absorption rate of iodoform and triiodophenol (124,125). Since potassium iodide is not solubilized by the micelle, the enhanced rate of absorption is attributed to the influence of the surfactant on the mucosal membrane. The other compounds, which partition into the micelle, exhibit a reduced rate of absorption since there is a decrease in their effective (i.e., unbound) concentration. Similar observations, using pharmacological response data in goldfish, have been made for several barbiturates in the presence of varying surfactant concentrations.

In addition to the aforementioned effects of surfactants, one must consider their influence on drug dissolution from pharmaceutical dosage forms. If the drug is poorly water soluble, enhanced dissolution rate in the presence of a surface-active agent, even if part of the drug is solubilized, will result in increased drug absorption. The absorption rate of sulfisoxazole suspensions given rectally to rats increased with increasing polysorbate 80 concentration. At surfactant concentrations in excess of that needed to solubilize the drug completely, there was a reduced rate of absorption; however, the rate was greater than that from the control suspension (i.e., without surfactant) (126).

Another important type of physical-chemical interaction, which may alter absorption, is that of drug binding or adsorption onto the surface of another material. As with complexation and micellarization, adsorption will reduce the effective concentration gradient between gut fluids and the bloodstream, which is the driving force for passive absorption. While adsorption frequently reduces the rate of absorption, the interaction is often readily reversible and will not affect the extent of absorption. A major exception is adsorption onto charcoal, which in many cases appears to be irreversible, at least during the time of residence within the GIT. As a result, charcoal often reduces the extent of drug absorption. Indeed, this fact along with the innocuous nature of charcoal is what makes it an ideal antidote for oral drug overdose. The effectiveness of that form of therapy will depend on the amount of charcoal administered and the time delay between overdose and charcoal dosing. Another interesting aspect of charcoal dosing is its influence on shortening the elimination halflife of certain drugs. This is a particularly attractive noninvasive means of enhancing drug elimination from the body for drugs that undergo enterohepatic recycling (phenobarbital is a good example).

In addition to charcoal, adsorption is often seen with pharmaceutical preparations that contain large quantities of relatively water-insoluble components. A good example is antidiarrheal products and perhaps antacids. The importance of the strength of binding as it influences absorption has been illustrated by Sorby (127), who showed that both attapulgite and charcoal reduce the rate of drug absorption but only charcoal reduced the extent of absorption. Lincomycin is an example of a drug whose absorption in impaired by an antidiarrheal preparation (128). Another type of compound that has been shown to alter drug absorption due to binding is the anion-exchange resins, cholestyramine and colestipol. The foregoing physical-chemical interactions, which may alter drug therapy, may be minimized by not coadministering the interacting compounds simultaneously but separating their ingestion by several hours.

Figure 18 Diagrammatic sketch indicating sites along the GIT where drug may be chemically altered or enzymatically metabolized. Source: Courtesy of Saguaro Press.
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