Luminal pH

The pH of the colon varies depending on the type of food ingested. In general, a drop in pH to 5.5 6.5 is monitored when a radiotelemetric capsule enters the colon [85,86]. This pH drop is caused by acidification of the colonic contents by bacterial fermentation (Table 1.1). 

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The glycocalyx and the mucus layer make up the structure of the unstirred water layer (UWL) [73]. The thickness of the UWL is estimated to be 30-100 pm in vivo, consistent with very efficient stirring effects [74]. In isolated tissue (in the absence of stirring), the mucus layer is 300-700 pm thick [73]. The pH in the unstirred water layer is 5.2-6.2, and might be regulated independently of the luminal pH (Section 2.3). The mucus layer may play a role in regulating the epithelial cell surface pH [73]. 

Nugent, S. G., Kumar, D., Rampton, D. S., Evans, D. F., Intestinal luminal pH in inflammatory bowel disease possible determinants and implications for therapy with aminosalicylates and other drugs, Gut 2001, 48, 571-577. 

Sasaki, Y., Hada, R., Nakajima, H., Fukuda, S., Munakata, A., Improved localizing method of radiopill in measurement of entire gastrointestinal pH profiles colonic luminal pH in normal subjects and patients with Crohn s disease, Am. J. Gastroenterol. 1997, 92, 114-118. 

At pH 4 most bacteria are killed within 30 min, and at physiological luminal pH, 99% of bacteria are killed within 5 min [14], Certain bacteria, like lactobacilli, are more acid-resistant, and some microbes survive the hostile gastric environment by colonizing luminal niches at the mucosal surface, protected by gastric bicarbonate secretion. This is the case for Helicobacter pylori, related spiral-... 

There is also a gradient from the low luminal pH through the mucus layer, under which gastric bicarbonate secretion maintains neutral conditions. Mechanically, this is explained by the acid secretion occurring like small finger-like ejections penetrating the thick gel-like mucus layer into the gastric lumen [27]. 

Similar to the PAMPA and the Caco-2 models, the experimental pH of the buffer solution can be changed in the Ussing chambers model. However, it seems that the impact of changing the pH of the mucosal (= apical) buffer solution is lower than for the other two systems [82], This is probably due to the presence of the mucus layer retaining the microclimate pH regardless of the luminal pH using the Ussing chambers technique [82],... 

Recently, an approach mimicking the GI tract and feasible for pharmaceutical dissolution studies has been published [47], Coming from the area of nutritional research, this approach reflects some promising aspects, such as relevant luminal pH values, peristalsis, luminal bacterial colonization, and relevant fluid volumes. However, permeation is only reflected by diffusion through hollow fiber membranes and thus is not in the scope of this chapter. Nevertheless, it will be interesting to see whether it will be possible to expand such a perfect in vitro device toward a more realistic intestinal epithelium. 

Figure 6.2 Two major surgical models of BO and OA, oesophagojejunostomy with gastric preservation (A) and oesophagojejunostomy with total gastrectomy (B). Figure 2A shows intra-luminal pH values in the animals one week after esophagojejunostomy and preservation of the stomach (adapted from Fein al.).

Given the large number of variables, Thomas et argued that it was important to carry out both univariate and multi-variate analyses of the data. Both types of analysis showed that LBTT, the activity of the 7a-dehydroxy-lation, and the distal colonic luminal pH were all significant risk factors for high proportions of DCA in serum (and by implication, in bile). Based on these results, the authors concluded that there was indeed prolonged colonic transit in conventional gallstone patients and that this, in turn, was likely to result in increased DCA formation, solubilisation (and therefore bioavailability) and absorption. 

The fact that the luminal pH of the healthy distal colon is slightly higher than that of the proximal small intestine has led to the development of oral dosage forms that are intended to release the drug at the colonic pH (pH-controlled drug release). 

Time-controlled drug release with pH-induced drug delivery is a delivery method that does not depend on changes in the luminal pH of the GI tract but on a pH change within the dosage form itself. 

Jacobs. L.R. Lupton, J.R. (1986) Relationship between colonic luminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treated rats fed high fiber diets. Cancer Res.. 46, 1727-1734... 

Passive diffusional permeability was the same along the entire gastrointestinal tract, as the experiments were performed at the same luminal pH value. 

The Heidenhain pouch preparation was used by Carter and Grossman (1978), Kauffman et al. (1980) to study the effect of luminal pH on acid secretion evoked by topical and parenteral stimulants and the effect of topical and intravenous 16,16-dimethyl prostaglandin E2 on gastric bicarbonate secretion. 

The results presented by these experiments fall to support the concept that a single low-molecular weight, naturally occurring species (ligand) uniquely enhances zinc absorption. The different compounds had various effects on both mucosal uptake and retention and portal transfer of zinc that were dependent upon both luminal pH and concentration of the ligand. In recent studies. Hurley al. reported no effect of various ligands on zinc concentrations in rat dams and pups (40). Moreover, these perfusion data reaffirm the finding that EDTA enhances zinc absorption (41,42). 

In another study of stress ulcer prophylaxis, 53 critically ill patients were randomized to receive sucralfate 1 g 6-hourly, cimetidine 300 mg 8-hourly, or cimetidine 900 mg/day by continuous intravenous infusion (14). Although bacterial colonization was increasingly likely in patients with a persistent alkaline gastric environment, gastric luminal pH and the degree of bacterial colonization of the stomach were similar in the three groups. 

Weak acids increased excretion at luminal pH >7 Weak bases increased excretion at luminal pH <5... 

The bulk luminal pH is heavily affected by the fermentation of carbohydrates to short-chain fatty acids however, near the colonic mucosa, the pH rises and changes in the bulk pH have little effect on the epithelial microclimate. Bicarbonate/chloride exchange is partly responsible for raising the pH against the challenge posed by the high colonic pCOi and the acid production by fermentation. The mucus has been shown to contain a distinct carbonic anhydrase, produced by epithelial tissues that help to carefully regulate the thick unstirred layer of the colonic epithelium. 

In addition to mucus from goblet cells, bicarbonate ions are secreted from the stomach to protect the gastric mucosa from gastric acid. Bicarbonate secretion occurs when the luminal pH is less than 2 and its release is regulated both neuronally and hormonally. 

Table 3. Drugs and Xenobiotics with clinically important urine pH-dependent elimination. Weak acids increased excretion at luminal pH > 7 Weak bases increased excretion at luminal pH < 5 ...

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