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


CONCLUSIONS
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.
Dirson
Grégoire
G
Clinical Pharmacy Unit (EA 2706; Barrières et passage des medicaments), University of Paris-Sud XI, 5 rue Jean-Baptiste Clément, Châtenay-Malabry, 92296, France.
Fernandez
Christine
C
Hindlet
Patrick
P
Roux
Françoise
F
German-Fattal
Michèle
M
Gimenez
François
F
Farinotti
Robert
R
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000480:Alkynes; D000818:Animals; D048588:Benzoxazines; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D003521:Cyclopropanes; D003524:Cyclosporins / Q000494:pharmacology; D004077:Digoxin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010078:Oxazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D003524:Cyclosporins; D010078:Oxazines; D010880:Piperidines; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C077022:S 9788; D004077:Digoxin; C507084:Abcb1b protein, mouse; D011802:Quinidine; C098320:efavirenz; C070272:valspodar