Review of theoretical passive drug absorption models: historical background, recent developments and limitations

In the drug discovery process the optimization of a promising lead to an orally bioavailable drug remains a difficult task. Recent progress in the understanding of the role of physicochemical properties in membrane permeability relevant to important processes such as drug absorption and blood-brain barrier crossing, brings rational drug delivery more within reach. In the last thirty years a number of theoretical transport and absorption models have been developed to describe mathematically how a drug is being passively transported from its site of administration to its site of action and how a compound passes a membrane. The goal of such models is to rationalize the physical significance of the observed non-linear structure-permeability relationships. The models are based on various views on the composition of the biological membranes and on the underlying diffusion and distribution mechanisms. Often simplifications reducing the mathematical complexity are made. We review here a selection of the most important models and discuss modern views on the role of lipophilicity and various pathways through membranes.