title: Investigating ABCB1-Mediated Drug-Drug Interactions: Considerations for In vitro and In vivo Assay Design.
abstract: BACKGROUND
  ABCB1 is a key ABC efflux transporter modulating the pharmacokinetics of a large percentage of drugs. ABCB1 is also a site of transporter mediated drug-drug interactions (tDDI). It is the transporter most frequently tested for tDDIs both in vitro and in the clinic.
  
  
  OBJECTIVE
  Understanding the limitations of various in vitro and in vivo models, therefore, is crucial. In this review we cover regulatory aspects of ABCB1 mediated drug transport as well as inhibition and the available models and methods. We also discuss protein structure and mechanistic aspects of transport as ABCB1 displays complex kinetics that involves multiple binding sites, potentiation of transport and probe-dependent IC50 values.
  
  
  RESULTS
  Permeability of drugs both passive and mediated by transporters is also a covariate that modulates apparent kinetic values. Levels of expression as well as lipid composition of the expression system used in in vitro studies have also been acknowledged as determinates of transporter activity. ABCB1-mediated clinical tDDIs are often complex as multiple transporters as well as metabolic enzymes may play a role. This complexity often masks the role of ABCB1 in tDDIs.
  
  
  CONCLUSIONS
  It is expected that utilization of in vitro data will further increase with the refinement of simulations. It is also anticipated that transporter humanized preclinical models have a significant impact and utility.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sáfár
authors.forename: Balázs
authors.initials: B
authors.lastname: Vaskó
authors.forename: Tasha K
authors.initials: TK
authors.lastname: Ritchie
authors.forename: Gábor
authors.initials: G
authors.lastname: Imre
authors.forename: Károly
authors.initials: K
authors.lastname: Mogyorósi
authors.forename: Franciska
authors.initials: F
authors.lastname: Erdő
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Rajnai
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Fekete
authors.forename: Péter
authors.initials: P
authors.lastname: Szerémy
authors.forename: László
authors.initials: L
authors.lastname: Muka
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Zolnerciks
authors.forename: Krisztina
authors.initials: K
authors.lastname: Herédi-Szabó
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ragueneau-Majlessi
authors.affiliation: Solvo Biotechnology, Gyár u. 2, Budaörs, 2040 Hungary. krajcsi@solvo.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D017277:Drug Approval; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations