Inhibition of P-glycoprotein: rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier

Pharm Res. 1998 Jul;15(7):993-1000. doi: 10.1023/a:1011913723928.


Purpose: The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent.

Methods: An in vitro model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes was used.

Results: We demonstrate that P-glycoprotein expression is upregulated by the presence of astrocytes. Uptake in the cells and transport across endothelial cell monolayers of vincristine, cyclosporin A and doxorubicin were studied. Using S9788 or verapamil as reversing agents, we found an increase in vincristine transport across the endothelial cell monolayers. On the other hand, the association of S9788 or verapamil with cyclosporin A failed to increase the transport of this drug. An increase in the transport of doxorubicin from luminal to abluminal compartment was also observed, due to endothelial cell monolayer breakdown.

Conclusions: Using this model, it is possible to predict the passage of a P-glycoprotein dependent drug to the brain or its sequestration in brain capillary endothelial cells when this drug is associated with a reversing agent, or its toxicity on the blood-brain barrier integrity.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • Animals
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Biological Transport / drug effects
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology*
  • Brain / blood supply*
  • Brain / metabolism
  • Calcium Channel Blockers / pharmacology
  • Cattle
  • Coculture Techniques
  • Cyclosporine / pharmacokinetics*
  • Doxorubicin / pharmacokinetics*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Immunosuppressive Agents / pharmacokinetics*
  • Piperidines / pharmacology*
  • Predictive Value of Tests
  • Rats
  • Triazines / pharmacology*
  • Verapamil / pharmacology
  • Vincristine / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Calcium Channel Blockers
  • Immunosuppressive Agents
  • Piperidines
  • Triazines
  • S 9788
  • Vincristine
  • Doxorubicin
  • Cyclosporine
  • Verapamil