October 21, 2004, 1^st Annual PhysChem Symposium: Early ADME and Medicinal Chemistry

Can we Identify Models for Brain Uptake and Intestinal Absorption

Michael H. Abraham (University College London)

Abstract

A large number of physicochemical and biochemical processes can be satisfactorily correlated and predicted by multiple linear free energy relationships that use a number of specific solute (drug) descriptors as the independent variables. These descriptors are: E the solute excess molar refraction, S the solute polarizability/dipolarity, A the solute hydrogen-bond acidity, B the solute hydrogen-bond basicity, and V the solute McGowan volume. These descriptors can be calculated from structure, so that predictions from structure can be made. The general LFER equation is:

SP = c + e.E + s.S + a.A + b.B + v.V                    (1)

Here SP is a solute (drug) property in a given system, such as log P for water-octanol partition, or log BB for blood-brain distribution. Since the five coefficients in eq (1) characterize the system under consideration, comparison of coefficients for different systems allows the systems to be graded in terms of 'nearness', both chemically and mathematically. The most useful techniques for visualization of systems as regards chemical 'nearness' are principal component analysis and non-linear mapping. A more rigorous method regards the five coefficients for various processes as points in five dimensional space, and simply computes the distance between the points. As regards mathematical 'nearness', the θ-parameter of Ishihama and Asakawa seems to be quite useful. Examination by these methods of a large number of systems that involve partition and diffusion enables the systems to be identified or rejected as model systems for human intestinal absorption, blood/brain distribution and brain permeation.

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