Quantitative Structure Permeability Relationship models

The rather time- and cost-expensive preparation of primary brain microvessel endothelial cells, as well as the limited number of experiments which can be performed with intact brain capillaries, has led to an attempt to predict the blood-brain barrier permeability of new chemical entities in silico. Artificial neural networks have been developed to predict the ratios of the steady-state concentrations of drugs in the brain to those of the blood from their structural parameters [117, 118]. A summary of the current efforts is given in Chap. 25. Quantitative structure-property relationship models based on in vivo blood-brain permeation data and systematic variable selection methods led to success rates of prediction of over 80% for barrier permeant and nonper-meant compounds, thus offering a tool for virtual screening of substances of interest [119]. 

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. 

Limitations of Quantitative Structure-Activity Relationship Models for Skin Permeability ). Some work has been performed on percentage absorbed data that may be more applicable to risk assessment. For instance, Roy et al. (1998) modeled the percentage of the appUed dose of polycyclic aromatic hydrocarbons that penetrated rat skin in vitro after 24 h (PADA) using log P and a second term for molecular size, Shadow 6 Area (SHDW6) ... 

LIMITATIONS OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODELS FOR SKIN PERMEABILITY... 

Keywords Skin permeability Percutaneous absorption Skin penetration Mathematical model Quantitative structure-activity relationships Permeability coefficient Human skin... 

In the assessment of the uptake of a chemical after dermal exposure, for instance, the dermal permeability of the skin is often estimated using the Potts-Guy quantitative structure-activity relationship (Guy Potts, 1992), which was derived from an experimental data set of in vitro measured steady-state skin permeations (Wilschut et al., 1995). Uncertainty in the use of a value for the skin permeation obtained this way comes from questions of how well a regression model based on Kow and molecular weight predicts the skin permeability of a chemical that was not in the original data set, and how representative the steady-state permeability measured in vitro is for a (possibly) non-steady-state permeability in vivo (see also IPCS, 2006b). 

In addition, traditional quantitative structure-activity relationship (QSAR) models were reported. Gozalbes et al. attempted to predict the blood-brain barrier permeabilities of four arylacetamides using linear discriminant analysis [65], while Medina-Franco et al. discriminated between active and inactive BCG compounds using two-dimensional (2D) and three-dimensional (3D) structural-similarity methods [66]. 

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS OF SKIN PERMEABILITY MODELING PERMEABILITY COEFFICIENTS... 

This QSPR model also provides a quantitative measure for the structure-property relationships observed by other researchers. For example, it is well known that the para isomer is almost always more permeable and less selective than is the meta. This effect is illustrated below for the isopropylidene and hexafluoro isopropylidene units. The para isomers are 50-100x more permeable and with only about 30-40% of the selectivity of the meta isomers. 

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