Pharmaceutical Research

, Volume 23, Issue 7, pp 1525–1532

Efavirenz Does Not Interact with the ABCB1 Transporter at the Blood—Brain Barrier

  • Grégoire Dirson
  • Christine Fernandez
  • Patrick Hindlet
  • Françoise Roux
  • Michèle German-Fattal
  • François Gimenez
  • Robert Farinotti
Research Paper

DOI: 10.1007/s11095-006-0279-5

Cite this article as:
Dirson, G., Fernandez, C., Hindlet, P. et al. Pharm Res (2006) 23: 1525. doi:10.1007/s11095-006-0279-5
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Purpose

This work characterizes the interactions between efavirenz (EFV) and P-glycoprotein (P-gp/ABCB1) at the blood–brain barrier (BBB) and predicts the possible consequences on the brain uptake of coadministered P-gp substrates.

Methods

The uptake of EFV was measured in whole brains of rat and mdr1a−/− and mdr1a+/+ mice, and in GPNT cells (rat brain endothelial cell line) with and without P-gp inhibitors (PSC833, S9788, Quinidine). The effect of a single dose or multiple doses of EFV on the P-gp functionality was evaluated in vivo and in vitro by measuring the brain and cell uptake of digoxin, completed by the analysis of the P-gp expression at the rat BBB after repeated administrations of EFV.

Results

Inhibition of P-gp did not alter the uptake of EFV in rat brain and GPNT cells. The EFV brain/plasma ratio in mdr1a−/− mice, lacking the expression of P-gp, was not different from that in mdr1a+/+ mice. Moreover, a single dose of EFV did not modify the uptake of digoxin in rat brain and GPNT cells. Finally, the 3-day exposure of GPNT cells to EFV did not have any effect on the uptake of digoxin. Similarly, the 7-day treatment with EFV did not change the uptake of digoxin in rat brain nor the expression of P-gp at the BBB.

Conclusion

EFV is strongly distributed in the brain, but is neither a substrate nor an inhibitor of the P-gp at the blood–brain barrier. On the other hand, EFV did not induce P-gp, allowing to sustain the brain accumulation of associated P-gp substrates such as protease inhibitors. These findings make EFV suitable for combinations circumventing the brain HIV-1 residency.

Key words

blood–brain barrier efavirenz efflux P-glycoprotein uptake 

Abbreviations

ARV

antiretroviral

BBB

blood–brain barrier

EFV

efavirenz

MDR

multidrug resistance

NNRTI

nonnucleoside reverse transcriptase inhibitor

P-gp

P-glycoprotein

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Grégoire Dirson
    • 1
  • Christine Fernandez
    • 1
    • 2
    • 5
  • Patrick Hindlet
    • 1
  • Françoise Roux
    • 3
  • Michèle German-Fattal
    • 4
  • François Gimenez
    • 1
  • Robert Farinotti
    • 1
    • 2
  1. 1.Clinical Pharmacy Unit (EA 2706; Barrières et passage des medicaments)University of Paris-Sud XIChâtenay-MalabryFrance
  2. 2.Pharmacy DepartmentPitie Salpetriere HospitalParisFrance
  3. 3.INSERM U705–CNRS UMR 7157University of Paris VII & V, Fernand Widal HospitalParis, cedex 10France
  4. 4.CNRS UMR 8078University of Paris-Sud XI, Surgical Center Marie-LannelongueLe Plessis-RobinsonFrance
  5. 5.Service PharmacieGroupe Hospitalier PITIE SalpetriereParisFrance

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