Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein

Pharm Res. 2001 Dec;18(12):1660-8. doi: 10.1023/a:1013358126640.


Purpose: MDR1 P-glycoprotein (P-gp) plays an important role in determining drug disposition. The purpose of the present study was to establish in vitro models to predict the in vivo function of P-gp.

Methods: As an in vitro method, the transcellular transport of 12 compounds across the monolayer of Caco-2- and MDR1-transfected cells was examined. The ability of these compounds to stimulate the ATP hydrolysis was also determined using the isolated membrane fraction expressing P-gp. As a parameter to describe the in vivo P-gp function, we calculated the brain-to-plasma concentration ratio of compounds in mdr1a/1b knockout mice divided by the same ratio in wild type mice.

Results: A good correlation was observed between the in vitro flux ratio across the monolayer and in vivo P-gp function for 12 compounds. Although all compounds that stimulated ATP hydrolysis were significantly transported by P-gp, some compounds were transported by P-gp without significantly affecting ATP hydrolysis.

Conclusion: Collectively, the in vitro flux ratio across monolayers of P-gp-expressing cells may be used to predict in vivo P-gp function. The extent of ATP-hydrolysis in vitro may also be a useful parameter for in vivo prediction, particularly for eliminating P-gp substrates in high-throughput screening procedures.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Biological Transport
  • Blood-Brain Barrier / physiology*
  • Caco-2 Cells
  • Cell Membrane Permeability / physiology
  • Dose-Response Relationship, Drug
  • Humans
  • Hydrolysis
  • LLC-PK1 Cells
  • Male
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Pharmaceutical Preparations / metabolism*
  • Swine
  • Tissue Distribution
  • Transfection


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Pharmaceutical Preparations
  • Adenosine Triphosphate