Structure-permeability relationship

D. Physicochemical Factors Affecting Structure-Permeability Relationships... 

Although the use of polymers as membrane materials has increased markedly (1-3), the development of structure/permeability relationship has lagged and is an important area of future investigations. 

Liang, E., J. Proudeoot, and M. Yazdanian. Mechanisms of transport and structure-permeability relationship of sulfasalazine and its analogs in Caco-2 cell monolayers, Pharm. Res. 2000, 17, 1168-1174... 

Ekins, S., G. L. Durst, R. E. Stratford, D. A. Thorner, R. Lewis, R. J. Loncharich, and J. H. Wikel. Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication, J. Chem. Inf. Comput. Sci. 2001, 41, 1578-1586... 

Anderson, B. D. and Raykar, P. V., Solute structure-permeability relationships in human stratum comeum, J. Invest. Derm., 1989, 93, 280-286. 

Jung SJ, Choi SO, Urn SY, Kim JI, Choo HY, Choi SY and Chung SY (2006) Prediction of the Permeability of Drugs Through Study on Quantitative Structure-Permeability Relationship. J Pharm BiomedAnal 41 pp 469 175. 

Despite the availability of other cell lines, Caco-2 cells remain the most widely used intestinal cell culture model at present. This model has provided valuable information necessary for lead optimization in the drug discovery process. However, it is important to understand that compounds with high permeability in this model are typically well absorbed, whereas compounds with low solubility and low permeability in this model may not necessarily be poorly absorbed in vivo. Although this type of positive selection limits the usefulness in providing a structure-permeability relationship, the Caco-2 model has the most effect in drug discovery when the screen is implemented early and in conjunction with other types of in vitro and in vivo permeability/absorption screens. 

Cronin MTD, Dearden JC, Moss GP, Murray-Dickson G (1999) Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur J Pharm Sci 7 325-330. 

Patel H, ten Berge W, Cronin MTD (2002) Quantitative structure-permeability relationships (QSPRs) for percutaneous absorption. Toxicol. In Vitro 16 299-317. 

Cronin MTD, Dearden JC, Gupta R, Moss GP (1998) An investigation of flux across polydimethylsiloxane membranes by use of quantitative structure-permeability relationship. J Pharm Pharmacol 50 143-152. 

LC/MS/MS techniques with selective and sensitive detection methods make it possible to quantitatively analyze samples from Caco-2 cell and PAMPA buffer matrices. A high-throughput permeability screen with robust LC/MS technology can quickly generate information about structure-permeability relationships that are extremely valuable in the lead optimization phase for the selection of pre-clinical candidates with favorable oral bioavailability properties. 

On the basis of their evaluation and our internal predictive VolSurf model [160] for this series (r 0.81, q 0.60, 4 PLS components), it can be concluded that factors like size and shape, which had previously been reported to affect paracellular permeability, are indeed important in the VolSurf PLS model to explain the local structure-permeability relationship of one particular scaffold. Hence, local statistical models provide a qualitative ranking of candidates, and thus are valuable for optimization of pharmaceutically relevant compounds, especially if combined with additional models to understand affinity, selectivity or any particular pharmacokinetic behavior. 

It is important to understand some limitations of in vitro artificial membrane and cell permeability assays when the data is used for compound selection and structure permeability relationship study. Therefore, before moving into the structure permeability relationship section, limitations of in vitro assays are discussed in this section. There are a number of other limitations of in vitro models which should be considered [3, 70[. 

Structure-Permeability Relationships in Solution-diffusion Membranes... 

Stern SA.Vaidyanathan R, Pratt JR (1990) Structure/permeability relationships of silicon-containing polyimides. J Membr Sci 49(1) 1... 

Guy RH, Potts RO (1992) Structure-permeability relationships in percutaneous penetration. Journal of Pharmaceutical Sciences, 81(6) 603-604. 

Based on the study of Sugano et al. (2000) and our predictive VolSurf model for this series, it can be concluded that factors like size and shape previously reported to affect paracellular permeability are indeed important to explain the local structure-permeability relationship of this chemotype. Usually, permeability via paracellular aqueous pore diffusion depends on the size of the solute and its diffusion coefficient in water. Another important factor is lipophilicity. Between intestinal absorption and both volume and lipophilicity, a negative correlation was reported for this series of thrombin inhibitors. In addition, hydrogen bonding properties and dipolarity are factors that determine... 

In addition to in vivo and in vitro experimentation, mathematical models and quantitative structure-permeability relationship (QSAR) methods have been used to predict skin absorption in humans. These models use the physico-chemical properties of the test compound (e.g. volatility, ionization, molecular weight, water/lipid partition, etc.) to predict skin absorption in humans (Moss et al 2002). The models are particularly attractive because of the low cost and rapidity. However, because of the above-mentioned factors influencing dermal absorption, mathematical models are of limited use for risk assessment purposes. Since these models are currently not accepted by regulatory agencies involved in pesticide evaluations, they will not be further discussed in this chapter. 

E.J. Hoffman, Subquality natural gas The resource and its potential. In Investigation of Structure Permeability Relationships of Silicone Membranes, Final Report, edited by Chi-long Lee, S.A. Stem, J.E. Mark, and E. Hoffman. Report No. GRI-87/0037. Chicago Gas Research Institute, 1987. Report available from the National Technical Information Service. 

El Tayar, N., Tsai, R.-S., Testa, B., Carrupt, P.-A., Hansch, C. and Leo, A. (1991a). Percutaneous Penetration of Drugs A Quantitative Structure-Permeability Relationship Study. JPharm.ScL, 80,744-749. 

Nakai, D., Hubatsch, I., Bergstrom, C., Ekegren, J., Larhed, M. and Artursson, P. (2008) Structure—permeability relationship for a series of HIV-protease inhibitors in intestinal epithelial (2/4/A1) cells (in preparation). 

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