Shapes of membrane permeability-lipophilicity curves: extension of theoretical models with an aqueous pore pathway.
The objective of this study was to rationalize the shape of membrane permeability-lipophilicity curves, when considering, in addition to the usual transcellular route, a parallel diffusion pathway through aqueous pores as present in biological membranes. The theoretical influence of different pH in donor and acceptor compartment and the molecular weight on the permeability curves was studied. We combined and extended two previously proposed absorption models, namely one describing diffusion through a simple membrane (two stagnant aqueous and two organic layers in series, no pores) as the sum of the two distribution steps at both membrane interfaces, and a second theoretical model considering the sum of different diffusional resistances through stagnant layers and membrane, respectively. Under certain conditions the equivalence of the two-step distribution model and the diffusional resistance model can be demonstrated. Incorporation of an aqueous diffusion pathway leads to an extended two-step distribution model. This theoretical membrane permeation model will permit a more physicochemical-based interpretation of permeation data and shows that combined log D values and molecular weight are important determinants for membrane transport processes through, e.g. Caco-2 monolayers and the mucosal GI membranes. We have demonstrated that the well-known sigmoidal permeability-lipophilicity relationship should be considered as a molecular weight-dependent set of sigmoidal relationships.
Camenisch
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F. Hoffmann-La Roche Ltd., Pharma Research-Molecular Design and Bioinformatics, CH-4070 Basel, Switzerland.
Folkers
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van de Waterbeemd
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H
D000465:Algorithms; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004058:Diffusion; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry*; D008962:Models, Theoretical; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010599:Pharmacokinetics; D016062:Porosity; D014867:Water / Q000378:metabolism
D008055:Lipids; D004364:Pharmaceutical Preparations; D014867:Water