Acid microclimate

Shiau et al. [73] directly measured the microclimate pH, pHm, to be 5.2-6.7 in different sections of the intestine (very reproducible values in a given segment) covered with the normal mucus layer, as the luminal (bulk) pH, pH/, was maintained at 7.2. Good controls ruled out pH electrode artifacts. With the mucus layer washed off, pHm rose from 5.4 to 7.2. Values of pHfo as low as 3 and as high as 10 remarkably did not affect values of pHm. Glucose did not affect pHm when the microclimate was established. However, when the mucus layer had been washed off and pHm was allowed to rise to pHfo, the addition of 28 mM glucose caused the original low pHm to be reestablished after 5 min. Shiau et al. [73] hypothesized that the mucus layer was an ampholyte (of considerable pH buffer capacity) that created the pH acid microclimate. 

Said et al. [78] directly measured the acid microclimate on the surface of gastrointestinal tract (GIT) epithelial cells (intact with mucus layer) in rats. The pH on the apical (donor) side of the cells varied from 6.0 to 8.0, while the pH on the basolateral (acceptor) side was 7.4. Furthermore, the pH gradient between... 

H Daniel, B Neugebauer, A Kratz, G Rehner. Localization of acid microclimate along intestinal villi of rat jejunum. Am J Physiol 248 G293-G298, 1985. 

Said et al. [32] directly measured the acid microclimate on the surface of gas-... 

J. A. Blair, A. J. Matty. Acid microclimate in intestinal absorption. Clin. Gastroenterol. 1974, 5, 183—197. 

Physiological Buffer Systems Recently, a lot of efforts have been made on how to increase the biorelevance of the Caco-2 model [63, 47, 64, 65,105], Historically, the media used for Caco-2 experiments were buffered at pH 7.4 on both sides of the monolayer. The pH in the cellular interstice and blood compartment is known to be 7.4. However, the pH in the upper GI tract under fasted conditions ranges from 5.0 to 6.5, with an acidic microclimate existing just above the epithelial cell layer estimated to be between 5.8 and 6.3 [90], The pH of the apical medium can have a critical effect on the transport of drugs, especially for drugs with a pKa close to 7, or when pH-dependent transporters are involved. 

In addition to the longitudinal pH gradient, there is a pH gradient starting with the lumen to the absorbing surface [109,110]. Because of this gradient, the pH at the mucosal surface of the small intestine is different from that of the luminal content (a decrease of at least 1 pH unit, e.g., from 7.1 to 6.1) [111,112]. It was shown that the acidic microclimate is an essential determinant in fatty acid uptake after micellization [113]. The presence of a low-pH compartment facilitates the dissociation of mixed micelles made up of taurocholate and oleic acid. The rate of fatty acid diffusion in the mucin layer was estimated to be 400% of that in a buffer solution [114]. 

Shiau, Y.F. 1990. Mechanism of intestinal fatty acid uptake in the rat The role of an acidic microclimate. J Physiol 421 463. 

The antibacterial enzyme lysozyme is also found in nasal secretions. Lysozyme is produced by the epithelium and mucus glands where it can attack the cell walls of susceptible microorganisms, its action being optimal at the slightly acidic microclimate pH. The pH of nasal mucus varies with age, sleep, rest, emotion, infection, and diet. When it is cold, or during rhinitis or sinusitis, the pH tends to be alkaline, which deactivates the lysozyme in mucus and therefore increases the risk of microbial infection. Under normal conditions, the nasal secretions, as indicated earlier, have a pH of 5.5 to 6.5, which is the optimum pH for the activity of lysozyme. 

Solubilization of lipid digestion products in intestinal mixed micelles enhances their dissolution and dramatically increases the GI lumen-enterocyte concentration gradient that drives absorption by means of passive diffusion. Micelles, however, are not absorbed intact [8, 9], and lipids are thought to be absorbed from a monomolecular intermicellar phase in equilibrium with the intestinal micellar phase [10], The dissociation of monomolecular lipid from the micellar phase appears to be stimulated by the presence of an acidic microclimate associated with the enterocyte surface [11,12], In addition to passive diffusion, growing evidence suggests that active uptake processes mediated by transport systems located in the enterocyte membrane are also involved in the absorption of (in particular) fatty acids into the enterocyte [4],... 

As indicated by the prevention of acid-induced physical aggregation of BSA in an abstract [212], three principal ways have been identified thus far to avoid the formation of highly acidic microclimate regions in the PLGAs during protein release ... 

Shenderova, A., Burke, T. G., and Schwendeman, S. P. (1999), The acidic microclimate in poly(lactide-co-glycolide) microspheres stabilizes camptothecins, Pharm. Res., 16, 241-248. 

Molecules move within the unstirred layers by diffusion at a rate inversely proportional to the square root of molecular weight below 450, and inversely proportional to the cube root of molecular weight above 450. The glycocalyx is negatively charged, with counterions in the unstirred layer. If a substantial proportion of these cations is composed of hydrogen ions, as is often the case, then the microclimate within the brush border of the epithelium is likely to be acidic relative to the bulk phase. This may influence drug ionization at the membrane surface, and provides a basis for the acid microclimate frequently associated with the GI mucosa. 

Hanisch G, Utter L, Ungell A-L, and Lucas M. Surface pH Measurements During in vitro Transport Studies Across Intestinal Epithelia Thickness of Acid Microclimate. AAPS annual meeting in San Diego, California, 6-10 Nov, 1994. Pharm Res.l994 ,vo 11 10 suppl. 

The stabilization effect of insoluble base on protein in PLGA microspheres has also been demonstrated (8), as shown in Table 4. BSA also was shown to form non-covalent aggregates ( 25-70%) when encapsulated in w/o/w PLGA microspheres, confirming that an acidic microclimate also commonly develops in PLGA 50/50 microspheres (41,43). Whereas the BSA... 

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