title: Applications of a 7-day Caco-2 cell model in drug discovery and development.
abstract: Oral delivery is the preferred route of administration and therefore good absorption after oral dosing is a prerequisite for a compound to be successful in the clinic. The prediction of oral bioavailability from in vitro permeability assays is thus a valuable tool during drug discovery and development. Caco-2 cell monolayers mimic the human intestinal epithelium in many aspects. These monolayers form tight junctions between cells and have been widely used as a model of human intestinal absorption. Caco-2 cells also express a variety of transporter proteins although the transformed nature of the cells results in unpredictable differentiation markers, transport properties and enzyme expression. Thus various modifications of the Caco-2 assay are used in laboratories across the globe. The purpose of this paper is to provide an overview of a time and resource saving 7-day Caco-2 assay protocol. We also discuss the impact of various experimental conditions on permeability measurements and its applications during lead optimization in early discovery and for clinical candidate characterization, specifically for prediction of absorption in human, at a later stage in drug development.
authors.affiliation: Hoffmann-La Roche Ltd., Pharma Research & Early Development, Global Formulation Research, Nutley, NJ, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Hoffmann-La Roche Ltd., Pharma Research & Early Development, Global Formulation Research, Nutley, NJ, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Yadava
authors.affiliation: Hoffmann-La Roche Ltd., Pharma Research & Early Development, Non-Clinical Safety, Basel, Switzerland; University of Eastern Finland, Faculty of Health Sciences, School of Pharmacy, Kuopio, Finland.
authors.forename: Aki T
authors.initials: AT
authors.lastname: Heikkinen
authors.affiliation: Hoffmann-La Roche Ltd., Pharma Research & Early Development, Non-Clinical Safety, Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: Hoffmann-La Roche Ltd., Pharma Research & Early Development, Global Formulation Research, Nutley, NJ, USA. Electronic address: asrailkar@gmail.com.
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
mesh_terms: D001681:Biological Assay; D018938:Caco-2 Cells; D055808:Drug Discovery; D006801:Humans; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations
keywords: 7-day Caco-2 assay; ADME; Absorption modeling and prediction; Caco-2 permeability; Lead optimization (LO); Prodrug