title: Experimental and computational screening models for the prediction of intestinal drug absorption.
abstract: The aim of this study was to devise experimental protocols and computational models for the prediction of intestinal drug permeability. Both the required experimental and computational effort and the accuracy and quality of the resulting predictions were considered. In vitro intestinal Caco-2 cell monolayer permeabilities were determined both in a highly accurate experimental setting (Pc) and in a faster, but less accurate, mode (Papp). Computational models were built using four different principles for generation of molecular descriptors (atom counts, molecular mechanics calculations, fragmental, and quantum mechanics approaches) and were evaluated for their ability to predict intestinal membrane permeability. A theoretical deconvolution of the polar molecular surface area (PSA) was also performed to facilitate the interpretation of this composite descriptor and allow the calculation of PSA in a simplified and fast mode. The results indicate that it is possible to predict intestinal drug permeability from rather simple models with little or no loss of accuracy. A new, fast computational model, based on partitioned molecular surface areas, that predicts intestinal drug permeability with an accuracy comparable to that of time-consuming quantum mechanics calculations is presented.
authors.affiliation: Department of Pharmaceutics, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Stenberg
authors.forename: U
authors.initials: U
authors.lastname: Norinder
authors.forename: K
authors.initials: K
authors.lastname: Luthman
authors.forename: P
authors.initials: P
authors.lastname: Artursson
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology*; D002463:Cell Membrane Permeability; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D017245:Foscarnet / Q000493:pharmacokinetics; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000502:physiology*; D007792:Lactulose / Q000493:pharmacokinetics; D008353:Mannitol / Q000493:pharmacokinetics; D008954:Models, Biological; D011887:Raffinose / Q000493:pharmacokinetics; D013499:Surface Properties; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002250:Carbon Radioisotopes; D014316:Tritium; D017245:Foscarnet; D008353:Mannitol; D007792:Lactulose; D002939:Ciprofloxacin; D014700:Verapamil; D011887:Raffinose