LAUSR

&NA; Overcoming the efflux mediated by ATP–binding cassette (ABC) transporters at the blood‐brain barrier (BBB) remains a challenge for the delivery of small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib to the brain. Inhibition of ABCB1 and ABCG2 at the mouse BBB improved the BBB permeation of erlotinib but could not be achieved in humans. BBB disruption induced by focused ultrasound (FUS) was investigated as a strategy to overcome the efflux transport of erlotinib in vivo. In rats, FUS combined with microbubbles allowed for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using elacridar (10 mg/kg i.v). The brain kinetics of erlotinib was studied using 11C‐erlotinib Positron Emission Tomography (PET) imaging in 5 groups (n = 4–5 rats per group) including a baseline group, immediately after sonication (FUS), 48 h after FUS (FUS + 48 h), elacridar (ELA) and their combination (FUS + ELA). BBB integrity was assessed using the Evan's Blue (EB) extravasation test. Brain exposure to 11C‐erlotinib was measured as the area under the curve (AUC) of the brain kinetics (% injected dose (%ID) versus time (min)) in volumes corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. EB extravasation highlighted BBB disruption in the left hemisphere of animals of the FUS and FUS + ELA groups but not in the control and ELA groups. EB extravasation was not observed 48 h after FUS suggesting recovery of BBB integrity. Compared with the control group (AUCBaseline = 1.4 ± 0.5%ID.min), physical BBB disruption did not impact the brain kinetics of 11C‐erlotinib in the left hemisphere (p > .05) either immediately (AUCFUS = 1.2 ± 0.1%ID.min) or 48 h after FUS (AUCFUS+48h = 1.1 ± 0.3%ID.min). Elacridar similarly increased 11C‐erlotinib brain exposure to the left hemisphere in the absence (AUCELA = 2.2 ± 0.5%ID.min, p < .001) and in the presence of BBB disruption (AUCFUS+ELA = 2.1 ± 0.5%ID.min, p < .001). AUCleft was never significantly different from AUCright (p > .05), in any of the tested conditions. BBB integrity is not the rate limiting step for erlotinib delivery to the brain which is mainly governed by ABC‐mediated efflux. Efflux transport of erlotinib persisted despite BBB disruption.