A drug administered in a solid form must dissolve in gastrointestinal contents and pass out of the stomach into the small intestine. It then has to gain access to the epithelium by convection of the luminal contents and diffusion across the unstirred microclimate. Finally it must cross the epithelium either by partitioning into the lipid membrane, by passing through water-filled channels or by combining with specific membrane-bound carriers. The residence of the formulation in the small intestine has to be long enough for complete absorption to take place. The principal permeability barrier is represented by the luminal surface of the brush border. Most drugs are absorbed by passive diffusion in their unionised state. The pH of the small intestine determines the degree of ionisation and hence controls the efficiency of absorption; this is the basis of the pH-partition theory of drug absorption which was discussed in Chapter 1. Protein binding at the serosal side of the epithelium helps maintain a concentration gradient by binding the absorbed drug, which is then removed by blood flow from the absorption site.
Gastric pH has been relatively well defined since it is accessible using a Ryle's tube, but fewer studies have investigated intestinal conditions. Data obtained using pH telemetry capsules indicate that the lumen of the proximal jejunum usually lies within the pH range 5.0 to 6.5, rising slowly along the length of the small intestine to reach pH 6 to 7, although high values in the range 7 to 9 have occasionally been found59.
Measurements using microelectrodes have shown that the pH in the mucosal fluid adjacent to the intestinal epithelium is between 4.5 and 6.0 depending on the luminal glucose concentration. This acid microclimate immediately adjacent to the intestinal epithelium contributes to the absorption of acidic drugs such as acetylsalicylic acid60. The majority of the drug is ionised at the pH of the intestinal contents but the molecule is less ionised immediately adjacent to the intestinal epithelium and hence absorption is rapid. Unfortunately, this hypothesis suggests that basic drugs would be poorly absorbed, which is not the case. Bases may be absorbed in an ionised form through the paracellular route, or they may interact with organic cations which have been found to be secreted from the blood into the lumen of the intestine.
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