RT Journal Article SR Electronic T1 Persistence of the ABC transporter-mediated efflux at the physically disrupted blood-brain barrier: a 11C-erlotinib PET imaging study in rats JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 64 OP 64 VO 59 IS supplement 1 A1 Sebastien Goutal A1 Sylvain Auvity A1 Matthieu Gerstenmayer A1 Fabien Caille A1 Irene Buvat A1 Benoit Larrat A1 Nicolas Tournier YR 2018 UL http://jnm.snmjournals.org/content/59/supplement_1/64.abstract AB 64Objectives: Efflux transporters of the ATP-binding cassette (ABC) superfamily, namely the P-glycoprotein (ABCB1) and the Breast Cancer Resistance Protein (ABCG2) form the “functional” component of the blood-brain barrier (BBB). They are known to restrict the transendothelial permeation of most tyrosine kinase inhibitors (TKIs) such as erlotinib through the intact BBB, thus limiting the clinical perspective of TKI-based therapy against brain malignancies. However, “physical” BBB disruption, highlighted by MRI and gadolinium-induced contrast enhancement in patients, is a common feature of many CNS lesions. This observation suggests an “opened” paracellular route (between adjacent endothelial cells) and a locally increased BBB permeation of small molecules. Physical BBB disruption may thus be hypothesized to overwhelm the ABCB1/ABCG2-mediated efflux at the BBB. The impact of “physical” BBB disruption on the ABCB1/ABCG2 function and further brain exposure to erlotinib remain to be elucidated. Methods: The brain kinetics of erlotinib was studied using 11C-erlotinib PET imaging in rats. Physical BBB disruption was achieved using a protocol based on focused ultrasound (FUS) combined with microbubbles, allowing for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using i.v elacridar (10 mg/kg), a potent ABCB1/ABCG2 inhibitor. The brain kinetics was studied in 4 groups (n=5 animals per group) including control, FUS only (FUS), elacridar only (ELA) and their combination (FUS+ELA). After PET acquisition, BBB integrity was assessed ex vivo using the Evan’s Blue (EB) extravasation test. The brain exposure to 11C-erlotinib was estimated in each hemisphere as the area under the time-activity curve (AUC) from 0 to 30 min of the brain kinetics (% injected dose (%ID) versus time (min)) of 11C-erlotinib in volumes of interest corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. Statistical comparison was performed using a 2-way ANOVA with “condition” and “hemisphere” as factors. Results: EB extravasation displayed the substantial BBB disruption in the left hemisphere of animals of the FUS and FUS+ELA groups but not in the control and ELA groups. Compared with baseline (AUCBaseline = 1.4 ± 0.5 %ID.min), elacridar significantly increased 11C-erlotinib brain exposure to the left hemisphere (AUCELA = 2.2±0.5 %ID.min, p<0.001). In the presence of a BBB disruption, the effect of elacridar was similar: AUCFUS+ELA was significantly higher (p<0.001) than AUCFUS (2.1±0.5 %ID.min versus 1.2±0.1 %ID.min, respectively). This confirmed the ABCB1/ABCG2 substrate property of erlotinib at the BBB. Physical BBB disruption did not impact the brain kinetics of 11C-erlotinib in the left hemisphere compared with the control group. AUCleft was never significantly different than AUCright in any of the tested conditions (p>0.05). Conclusions: Using 11C-erlotinib PET imaging, we showed that ABC-transporter efflux at the BBB may not depend on BBB integrity. The efflux of ABCB1/ABCG2 substrates like erlotinib may persist even when the BBB is physically disrupted. The absence of additional or synergistic effect between ABCB1/ABCG2 inhibition and BBB disruption confirms that ABC-transporter function is the major determinant of erlotinib brain kinetics, thus highlighting the predominance of the “functional” component barrier rather than the “physical” component in controlling the brain penetration of this compound. Therefore, FUS-induced BBB disruption is not a relevant strategy to transiently overcome ABC-transporter efflux at the BBB so as to improve the brain delivery of erlotinib and/or to locally potentiate the brain exposure, even in the presence of ABCB1/ABCG2 inhibition.