title: Kinetics of lipid bilayer permeation of a series of ionisable drugs and their correlation with human transporter-independent intestinal permeability.
abstract: For low molecular weight drugs, lipid bilayer permeation is considered the major route for in vivo cell barrier passage. We recently introduced a fluorescence assay with liposomes to determine permeation kinetics of ionisable compounds across the lipid bilayer by monitoring drug-induced pH changes inside the liposomes. Here, we determined the permeability coefficients (PFLipP, FLipP for "Fluorescence Liposomal Permeability") across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers of 35 ionisable drugs at pH6.0 and compared them to available in vivo human jejunal permeability (Peff) data. PFLipPvalues were furthermore compared with published Caco-2 cell permeability coefficients (PCaco-2), permeability coefficients determined with the parallel artificial membrane permeability assay (PAMPA) and with log D (pH6.0). The log PFLipP, corrected for predicted para-cellular diffusion, and log PCaco-2correlated best with log Peff, with similar adjusted R2(0.75 and 0.74, n=12). Our results suggest that transporter-independent intestinal drug absorption is predictable from liposomal permeability.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Hermann
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Neuhaus
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Virgine
authors.initials: V
authors.lastname: Micallef
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Hatibovic
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Hélène E
authors.initials: HE
authors.lastname: Aschmann
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Paech
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Rubén
authors.initials: R
authors.lastname: Alvarez-Sanchez
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland. Electronic address: stefanie.kraemer@pharma.ethz.ch.
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Electronic address: sara.belli@roche.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Belli
mesh_terms: D006801:Humans; D007583:Jejunum / Q000378:metabolism*; D008051:Lipid Bilayers; D010539:Permeability; D010599:Pharmacokinetics
chemical_list: D008051:Lipid Bilayers
keywords: Caco-2; FLipP; Fluorescence; Intestinal absorption; Liposomes; Permeability