Paracellular transport bioavailability

The enzymatic degradation of insulin was also shown to occur in the cytosol of alveolar cells, the pH optimum of the proteases being 7.4 [38]. To what extent intracellular proteases play a significant role in limiting the absorption of insulin is not clear, since the size of insulin likely allows paracellular transport over the alveolar epithelium. However, for proteins of higher molecular weight, that require transcellular transport, these proteases might certainly limit bioavailability. 

According to Gasteiger et al. [59], the correlation coefficient r between bioavailability and HIA is 0.498 for 161 compounds. This conclusion inspires us to propose the use of aqueous solubility, descriptors of HIA models, and some rule-based descriptors to predict first-pass metabolism, to model bioavailability. Another research direction for the prediction of oral bioavailability is to develop separate prediction models for different components involved in oral bioavailability, including passive transcellular transport, paracellular transport, carrier-mediated transport, and first-pass metabolism, and then integrate them together. At present, the development of an integrated model is really difficult or even impossible because the predictions for some mechanisms involved in oral bioavailability are really unreliable. 

There does not appear to be any significant proteolytic degradation by enzymes in the extracellular fluid in normal human airways and alveoli. However, the presence of peptidases makes absorption of small peptides variable and difficult to predict. Peptidase-resistant peptides generally show better bioavailabilities than other peptides with comparable molecular weights. ° Difference in metabolism and absorption of d and L forms of peptides glycyl-D-phenylalanine and glycyl-L-phenylalanine was demonstrated by Morimoto et al.f The l peptide was subject to metabolism, and it had significant paracellular transport with a smaller transcellular component. In contrast, the... 

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. 

The passive transport pathway is nonsaturable and paracellular. It occurs throughout the small intestine and is unaffected by calcium status or parathyroid hormone (PTH). It is relatively independent of 1,25(0H)2D3, although this metabolite has been foimd by some investigators to increase the permeability of the paracellular pathway. A substantial amoimt of calcium is absorbed by passive transport in the ileum due to the relatively slow passage of food through this section of the intestine. The amoimt of calcium absorbed by passive transport will be proportional to the intake and bioavailability of calcium consumed. 

Permeation across the intestinal wall involves both passive and facilitated processes. Passive transport includes passive transcellular permeation and paracellular diffusion across cell junctions, while facilitated transport includes active influx and efflux processes that pump molecules in and out of the cells. In order to improve absorption of a molecule, engineering passive permeability is a preferred strategy over engineering affinity to an influx transporter. The expression levels of active transporters vaiy significantly between different tissues and individuals, and the specificities and expression levels vaiy among mammals, which decreases the ability to predict human PK based on animal studies. In contrast, passive membrane permeability basically works the same with any eukatyotic membrane, although there may be minor quantitative differences due to different membrane compositions. As paracellular permeation is mainly pertinent to small and polar molecules, passive membrane permeability, which is crucial to transcellular diffusion, is therefore one of the kty properties that needs to be optimized for developing bioavailable macrocycles. 

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