Efavirenz does not interact with the ABCB1 transporter at the blood-brain barrier.

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.