Lipophilicity and Related Molecular Properties as Determinants of Pharmacokinetic Behaviour
Keywords:Hydrogen bonding capacity, Intramolecular interactions, Intermolecular forces, Lipophilicity, Pharmaceutical chemistry, Pharmacokinetic behaviour
This minireview presents some recent work, mainly from the authors' laboratory, aimed at improving the interpretability and predictivity of structure-pharmacokinetic relationships. The first part of the text discusses the intermolecular forces and intramolecular interactions encoded in lipophilicity, with emphasis on the hydrogen-bonding capacity of bioactive compounds. Three-dimensional molecular fields provide a most informative and relevant description of molecular structure and properties, particularly the Molecular Lipophilicity Potential (MLP) and our novel Molecular Hydrogen Bonding Potentials (MHBPs), both of which are computed from experimentally derived atomic increments.
The second part of the paper discusses selected structure-pharmacokinetic relations, illustrating how permeation processes are influenced by the H-bonding capacity of permeants. Thus, lipophilicity-derived H-bonding parameters are found to correlate with skin permeation and brain penetration. Similarly, the donor MHBP provides a promising correlation with oral absorption data in humans.
Although structure-metabolism relations are not discussed here, we summarise investigations showing how metabolic N-oxygenation modifies the physicochemical properties of pyridines and tertiary arylalkylamines, and hence may influence their distribution and excretion.
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