Metabolism and Transporters Drug Drug and Drug Nutrient Interactions

Drug molecules may be chemically or metabolically altered at various sites along the GIT, including within gut fluids, within the gut wall, and by microorganisms present in the low end of the tract. These sites are noted in Figure 18. Several examples of enzymatic alteration of certain drugs in gut fluids have been noted previously. Gut fluids contain appreciable quantities of various enzymes, which are needed to accomplish digestion of food. An additional consideration in that regard is that of acid- or base-mediated drug breakdown. Numerous drugs are unstable in acidic media (e.g., erythromycin, penicillin) and will therefore degrade and provide lower effective doses depending on the pH of the gastric fluid, solubility of the drug, and the residence time of the dosage form in the stomach. Chemical modification of the drug by, for example, salt or ester formation may provide a more stable derivative whose absorption will be influenced to a smaller degree by the factors noted above. An interesting example of a prodrug that must first be acid-hydrolyzed to produce the active chemical form is clorazepate. Upon hydrolysis in the gut fluids, the active form, N-desmethyldiazepam, is produced. In this instance, unlike the examples cited above, acid hydrolysis is a prerequisite for absorption of the pharmacologically active form. As a result, pH of gastric fluids and gastric-emptying time and variables that influence those factors are expected to affect the absorption profile of clorazapate. Greater concentrations of N-desmethyldiazepam are achieved at the lower gastric pH, which is consistent with the more rapid acid hydrolysis at acidic pH (129).

As noted in a preceding section, mucosal cells lining the gut wall represent a significant potential site for drug metabolism. The metabolic activity of this region has been studied by a variety of techniques, ranging from subcellular fractions to tissue homogenates to methods involving the whole living animal. Metabolic reactions include both phase I and phase II processes. It appears that the entire small intestine, especially the jejunum and ileum, have the greatest enzymatic activity, although most regions of the GIT can partake in metabolism. It is not a simple matter, especially in the whole animal, to distinguish among the several sites of metabolism responsible for "presystemic elimination." The latter refers to all processes of chemical or metabolic alteration prior to the drug reaching the systemic circulation, which take place primarily in the gut and liver (first-pass effects). It is this presystemic elimination that contributes to differences in drug effects as a function of route of administration, and which may seriously compromise the clinical efficiency of certain drugs given orally. There are many drugs that have been shown to undergo extensive metabolism in the gut wall, including, among others, atorvastatin, simvastatin, felodipine, buspirone, midazolam, cyclosporine, and tacrolimus (130). L-Dopa appears to be metabolized by decarboxylase enzymes present in the gastric mucosa, which, as discussed previously, suggests the importance of rapid gastric emptying to achieve maximal absorption of the unchanged compound (131).

Salicylamide and p-aminobenzoic acid are interesting examples because they illustrate another aspect of gut metabolism, which is that of saturation. In addition, factors affecting absorption rate, such as the presence of food, will influence the fraction of the dose reaching the systemic circulation in the form of intact drug. Figure 19 illustrates the relationship between the area under the salicylamide plasma concentration-time curve as a function of the oral dose of sodium salicylamide (132). Normally, that relationship is expected to be linear, and the line should go through the origin. The curvilinearity, especially at low doses, suggests some form of presystemic elimination, which becomes

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Eliminating Stress and Anxiety From Your Life

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