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.
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Abbreviations
- ARV:
-
antiretroviral
- BBB:
-
blood–brain barrier
- EFV:
-
efavirenz
- MDR:
-
multidrug resistance
- NNRTI:
-
nonnucleoside reverse transcriptase inhibitor
- P-gp:
-
P-glycoprotein
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Acknowledgments
This research project was granted by the doctoral CIFRE convention no. 651/2003 established between the Infectiology & Immunology Department (Thu Huyen Nguyen, MD, and Dan Chiche, MD) of the Bristol-Myers Squibb group (Rueil-Malmaison, France), the National Association for Technical Research (Paris, France) and the Clinical Pharmacy Unit (EA 2706; Châtenay-Malabry, France). We would like to thank Pr. J.C. Gantier and Dr. M. Buyse for expert assistance in animal experimentations, and Dr H. Chacun for technical support in radioactivity studies.
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Dirson, G., Fernandez, C., Hindlet, P. et al. Efavirenz Does Not Interact with the ABCB1 Transporter at the Blood—Brain Barrier. Pharm Res 23, 1525–1532 (2006). https://doi.org/10.1007/s11095-006-0279-5
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DOI: https://doi.org/10.1007/s11095-006-0279-5