| Abstract [eng] |
The objective of this work was to develop mechanistic quantitative structure activity relationship models that would facilitate the assessment of drug properties related to their absorption and distribution in the body. The analysis involved several parameters reflecting the rate of passive diffusion across brain endothelium and intestinal epithelium, and thermodynamic constants related to drug distribution between plasma and tissues. Permeation through cellular transport barriers was modeled by nonlinear equations relating the passive diffusion rate to physicochemical properties of drugs: lipophilicity, ionization, hydrogen bonding potential and molecular size. It was demonstrated that brain endothelium and intestinal epithelium exhibit a quantitatively similar pattern of permeability-ionization dependence – ionized species permeate 2-3 orders of magnitude slower than neutral molecules. Analysis of tissue to plasma partitioning data revealed the necessity to split original experimental values into separate terms reflecting plasma and tissue binding strength. Drugs’ affinity to tissues could then be described by their lipophilicity, whereas detrimental effect of ionization was only observed for acidic drugs. Finally, it was shown that a linear combination of quantitative blood-brain barrier transport parameters allows classifying drugs according to their access to central nervous system with 94% overall accuracy. |
