Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight.
A recently developed, new theoretical absorption model for passive diffusion through biological membranes describing the dependency of membrane permeability on lipophilicity and molecular size, predicts different sigmoid-hyperbolic permeability-lipophilicity relationships for different molecular weight ranges. This model has been tested with experimental in vitro cultured epithelial cell (Caco-2) permeability data for structurally diverse drugs differing in lipophilicity, ionization state and molecular size. These data were pooled with literature values. Using this simple physicochemical approach, the permeability of a compound through Caco-2 cells by passive diffusion can be predicted from the compounds' distribution coefficient in 1-octanol/water (log D(oct)) and its molecular weight (MW). Deviations from this expected behaviour may point to the involvement of biological components in the transport process, which may require further investigations.
Camenisch
G
G
F. Hoffmann-La Roche Ltd., Pharma Research-Molecular Design and Bioinformatics, CH-4070 Basel, Switzerland.
Alsenz
J
J
van de Waterbeemd
H
H
Folkers
G
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry; D000465:Algorithms; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004058:Diffusion; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018435:ATP Binding Cassette Transporter, Subfamily B; D008055:Lipids; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A