Small intestine, selective permeability

Thus, the apparent membrane permeability characteristics of hydrophilic compounds listed in Table 3.4 indicate that colonic epithelium is different from small intestinal epithelium in selectivity, or size or density distribution of the paracellular pathway. This is further complicated because of the possible involvement of unidentified carriers or channels for some compounds, as suggested for glycerol and D-xylose. However, the colon-to-SI ratios of the apparent membrane permeability are generally comparable with (or lower than) those calculated considering the morphological surface area, suggesting that such factors are not in favor for colonic absorption in most cases. Matching... 

CRITICAL ASSESSMENT OF THE METHOD VolSurf descriptors are able to predict absorption for a diverse set of drugs. The presented model is derived using a consistent frame of relevant chemically interpretable descriptors, which find applications in different local and general models. However, absorption is not only controlled by passive membrane permeability. There are other factors influencing in vivo human absorption namely the in vivo dissolution rate in small intestinal fluid and the dose used for the human study. Furthermore, active transport or efflux mechanisms are difficult to rule out but can only be partially monitored by in vitro experiments. These important pieces of information should be known before any QSAR analysis is attempted on human absorption. This lack of consistent information throughout the literature is difficult to overcome, in particular for human studies. Hence, this study for the dataset from Zhao et al. (2001) provides a reasonable attempt to address these problems to carefully selecting members of the final dataset. 

Prognosis of a compounds permeability should be made stressing limitations of the model. There is no bioavailability prognosis from in vitro data - a cellular assay can provide only permeability potential through a biological membrane. The membrane, in most cases CACO-2 cells, is very similar to what we observe in vivo in the small intestine and resembles many characteristics to in vivo enterocytes. CACO-2 cells can be used for prediction of different pathways across intestinal cells. Best correlation occurs for passive transcellular route of diffusion. Passive paracellular pathway is less permeable in CACO-2 and correlations are rather qualitative than quantitative for that pathway. CACO-2 cells are an accepted model for identification of compounds with permeability problems, for ranking of compounds and selection of best compounds within a series. Carrier-mediated transport can be studied as well using careful characterization of transporters in the cell batch or clone as a prerequisite for transporter studies. 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

Lennemas et al. have developed a method for measuring human effective permeability (H-Peff) using a regional intestinal perfusion technique. In this method, a perfusion apparatus consisting of a multichannel tube with two inflatable balloons (10 cm apart) is swallowed by the patient and eventually located in the proximal jejunum. Dilute solutions of the test drag are introduced at the inlet located at the center of the 10 cm section, and the loss of drag is determined from the concentration in the outlet intestinal perfusate. In such a fashion, the H-Peff for 22 carefully selected drug molecules has been determined and a theoretical model of H-Peff has been developed. " The small size of the published H-Peff database is most likely due to the expense of the human measurement. 

To increase the utility and selectivity of gas-sensing electrodes, another membrane (e.g., pig intestine or collagen serving as a support) with an immobilized enzyme can be placed over a hydrophobic gas-diffusion membrane. A sample is usually injected into a small mixing chamber with the electrode. The immobilized enzyme is then exposed to an analyte and the enzymatic reaction produces a pH-changing gas, which diffuses both back to the sample and towards the pH sensor (through the enzyme support and the gas-permeable membrane). 

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