title: In vitro and in vivo approaches to characterize transporter-mediated disposition in drug discovery.
abstract: BACKGROUND
  It is becoming increasingly evident that transporters play an important role in the absorption, distribution and elimination of many drugs. Different approaches have been developed and validated to understand the interactions between drugs and transporters, and the in vivo role of drug transporters. These tools are helping to understand the impact of transporters on the pharmacokinetics (PK) of drugs and assess the risk of drug-drug interactions (DDIs) in drug discovery and development.
  
  
  METHODS
  This article provides an overview of different approaches to evaluate the drug transporters involved in intestinal absorption, hepatic and renal clearance, and brain penetration. Specifically, it provides the best practices to evaluate the major uptake and efflux transporters in drug discovery. It also discusses the challenges and gaps in understanding the clinical relevance of drug transporters.
  
  
  CONCLUSIONS
  Quantitative prediction of transporter-mediated clearance, tissue exposure, as well as DDIs is still limited. The current challenge is to develop in vitro-in vivo correlations, extrapolate and integrate data from in vitro transporter assays, and preclinical species into humans to quantitatively predict the impact of transporters on drug absorption, disposition, elimination and DDIs. With the development of a variety of novel tools, the ultimate goal is to use high quality in vitro and in vivo data to establish physiologically based PK models, which will improve the capability to predict PK, tissue exposure and DDIs in humans.
authors.affiliation: Pfizer, Inc., Pharmacokinetics, Dynamics and Drug Metabolism (PDM) , Eastern Point Road, Groton, CT 06340 , USA +1 860 715 2756 ; bo.feng2@pfizer.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Manthena V
authors.initials: MV
authors.lastname: Varma
authors.forename: Chester
authors.initials: C
authors.lastname: Costales
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Larry
authors.initials: L
authors.lastname: Tremaine
mesh_terms: D000818:Animals; D001692:Biological Transport; D015195:Drug Design; D055808:Drug Discovery; D004347:Drug Interactions; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
chemical_list: D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations
keywords: drug transporters; drug–drug interactions; in vitro tools; pharmacokinetics