Permeability Studies

The specific surface area of a solid is one of the first things that must be determined if any detailed physical chemical interpretation of its behavior as an adsorbent is to be possible. Such a determination can be made through adsorption studies themselves, and this aspect is taken up in the next chapter there are a number of other methods, however, that are summarized in the following material. Space does not permit a full discussion, and, in particular, the methods that really amount to a particle or pore size determination, such as optical and electron microscopy, x-ray or neutron diffraction, and permeability studies are largely omitted. 

FIG. 7 Schematic drawing illustrating the structure of (a) native or glutaraldehyde-treated S-layer containers as prepared for permeability studies according to the space technique and of (b) S-layer ultrafiltration membranes. 

FS Horn, SA Veresh, WR Ebert. Soft gelatin capsules II. Oxygen permeability study of capsule shells. J Pharm Sci 64 851-857, 1975. 

Kansy, M. Fischer, H. Kratzat, K. Senner, F. Wagner, B. Parrilla, I., High-throughput aritificial membrane permeability studies in early lead discovery and development, in Testa, B. van de Waterbeemd, H. Folkers, G. Guy, R. (eds.), Pharmacokinetic Optimization in Drug Research, Verlag Helvetica Chimica Acta, Zurich and Wiley-VCH Weinheim, 2001, pp. 447 164. 

In vivo Permeability Studies in the Gastrointestinal Tract of Humans... 

Kahns, A. H., Moss, J., Bundgaard, H., Human skin permeability studies... 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

Gryns (1896), Hedin (1897), and especially Overton (1900) looked at the permeability of a wide range of different compounds, particularly non-electrolytes, and showed that rates of penetration of solutes into erythrocytes increased with their lipid solubility. Overton correlated the rate of penetration of the solute with its partition coefficient between water and olive oil, which he took as a model for membrane composition. Some water-soluble molecules, particularly urea, entered erythrocytes faster than could be attributed to their lipid solubility—observations leading to the concept of pores, or discontinuities in the membrane which allowed water-soluble molecules to penetrate. The need to postulate the existence of pores offered the first hint of a mosaic structure for the membrane. Jacobs (1932) and Huber and Orskov (1933) put results from the early permeability studies onto a quantitative basis and concluded molecular size was a factor in the rate of solute translocation. 

Ewe K, Wanitscke R and Staritz M (1984) Intestinal Permeability Studies in Humans. In TZ Csaky (Ed.), Pharmacology of Intestinal Permeation II. New York, Springer-Verlag, pp 535-571. 

The buccal mucosa does serve as an alternative route for administering compounds systematically however, to ensure particular compounds are candidates for delivery across this biological tissue, preclinical screening is essential. While in vivo human permeability studies are ideal, due to their costs and associated issues, it is necessary to perform such screening in vitro. Assessment of compound permeability across porcine buccal mucosa has been widely used and can provide the preclinical biopharmaceutical scientist with much information relating to permeability, routes of transport, and effects of various chemical penetration enhancers. 

The ex vivo methods lend themselves easily for the performance of mechanistic investigations. In order to optimize selection of drug candidates prior to further clinical development, it is important to decipher the contributive roles of permeation, metabolism, efflux, and toxicity. This will then make it possible to properly channel the optimization process, for instance, by permeation enhancement, mucoadhesion, modification of the physicochemical characteristics of the drug, or even change in the route of administration in case the drug and/or formulation turns out to be too toxic. Regarding permeability studies, it is possible not only to quantify passive diffusion but also to identify and characterize (compound)-specific carrier-mediated transport routes. These tools have been used to identify and characterize the relative contribution of... 

Permeability Studies and Characterization of Drug Absorption Pathways... 

Miniaturization Currently, permeability studies using cell mono-layers are conducted in automation-friendly 12- or 24-well multiwell plates. Unfortunately, further miniaturization (96- or 384-well cell models) has been technically difficult to achieve because of the small surface area of the... 

Kansy M, Fischer H, Kratzat K, Senner F, Wagner B, Parrilla I (2001) High-throughput artificial membrane permeability studies in early lead discovery and development. In Testa B, Van de Waterbeemd H, Folkers G, Guy R (Eds) Pharmacokinetic Optimization in Drug Research. Biological, Physicochemical and Computational Strategies. Wiley-Interscience, Hoboken, pp 447 -64. 

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