title: Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety.
abstract: The drastic increase in the costs for discovering and developing a new drug and the high attrition rate of development candidates led to shifting of drug discovery strategy to parallel assessment of comprehensive drug properties along with efficacy. The article reviews the benefits and caveats of implementing comprehensive in vitro tools in early drug discovery and their impact on addressing in vivo ADMET issues. With the proposal of four-barrier profiling paradigm and employment of integrated risk assessment, one can exponentially enhance the predictive power of those in vitro tools by taking into consideration the interplays among those profiling parameters. An 'Exposure Cube' is proposed to promote collective employment of solubility/dissolution, permeability and metabolic clearance to address in vivo exposure and to direct optimization of new chemical entities in drug discovery.
authors.affiliation: Novartis Institutes for Biomedical Research, Metabolism and Pharmacokinetics, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Jianling.wang@novartis.com
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.forename: Laszlo
authors.initials: L
authors.lastname: Urban
authors.forename: Dejan
authors.initials: D
authors.lastname: Bojanic
mesh_terms: D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008657:Metabolic Clearance Rate; D004364:Pharmaceutical Preparations / Q000737:chemistry; D012995:Solubility; D014116:Toxicology
chemical_list: D004364:Pharmaceutical Preparations