title: In vitro ADME phenotyping in drug discovery: current challenges and future solutions.
abstract: Drug-metabolizing enzymes and drug transporters are key regulators of drug disposition and pharmacodynamics, which are closely linked to drug efficacy and safety. In this article, current challenges and future solutions to predicting their influence on pharmacokinetics and inter-organ distribution in humans, from data generated during the drug discovery decision-making process, are presented. In vitro phenotyping strategies for drug metabolizing enzymes (eg, CYP3A4, UGT1A1) and transporters (eg, OATP1B1) are offered, including perspectives on a selection of in vitro systems, novel in vitro phenotyping reagents and remaining technology gaps, challenges in extrapolating in vitro data to the in vivo situation, in silico models for the prediction of whether compounds are enzyme or transporter substrates, and the impact of pharmacogenomics.
authors.affiliation: Pfizer Global Research and Development, Pharmacokinetics, Dynamics and Metabolism, Ann Arbor, MI 48103, USA. james.williams2@pfizer.com
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Williams
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bauman
authors.forename: Hongliang
authors.initials: H
authors.lastname: Cai
authors.forename: Kevin
authors.initials: K
authors.lastname: Conlon
authors.forename: Steven
authors.initials: S
authors.lastname: Hansel
authors.forename: Susan
authors.initials: S
authors.lastname: Hurst
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: Meera
authors.initials: M
authors.lastname: Tugnait
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Jasminder
authors.initials: J
authors.lastname: Sahi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; D004798:Enzymes; D004364:Pharmaceutical Preparations