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Lipophilicity and Other Parameters Affecting Brain Penetration

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Over the past 50 years a number of efforts have been made to relate physicochemical parameters to the ability of molecules to cross the blood-brain barrier. Predominantly drugs enter the brain cells by transcellular passive diffusion through cells while paracellular transport is not considered significant due to the tight junctions between cells. Early work focused on correlations of brain uptake with a measured value of lipophilicity. Computational models were developed to model this parameter and the important structural characteristics of molecules, e.g. size and hydrogen-bonding capacity. New molecular descriptors, such as polar surface area and solvent free energies, have been generated and used. Practical methodology for predicting passive diffusion has also diversified with the use of cell monolayers and artificial membranes. These methods need to be validated against appropriate in vivo data and there is a need to consider the brain penetration data itself. Brain uptake is often expressed as partitioning of drugs into whole brain from blood or plasma, but the usual receptor targets for drugs are in the aqueous environment, extra-cellular fluid (ECF) surrounding the cell. In the brain, ECF concentrations are generally regarded to be reasonably well represented by cerebro-spinal fluid (CSF) concentrations. However there is limited literature data on CSF concentrations. In the blood-brain barrier the transporter P-glycoprotein (P-gp) is known to limit brain-uptake of certain compounds. In addition some compounds, including sugar and amino acids, may be actively transported into the brain. Models for brain penetration in the future are likely to include a number of in silico computed parameters or a number of physical measurements to allow contributions of passive and active transport to be considered.
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Keywords: Brain Penetration; Hydrogen Bonding; Lipophilicity

Document Type: Review Article

Publication date: September 1, 2002

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