--- res: bibo_abstract: - P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood–brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [11C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [11C]erlotinib in the brain (VT,brain) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [11C]erlotinib brain distribution were lower than in Abcb1a/b(−/−)Abcg2(−/−) mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug–drug interactions due to transporter inhibition in clearance organs question the translatability of this concept.@eng bibo_authorlist: - foaf_Person: foaf_givenName: Alexander foaf_name: Traxl, Alexander foaf_surname: Traxl - foaf_Person: foaf_givenName: Severin foaf_name: Mairinger, Severin foaf_surname: Mairinger - foaf_Person: foaf_givenName: Thomas foaf_name: Filip, Thomas foaf_surname: Filip - foaf_Person: foaf_givenName: Michael foaf_name: Sauberer, Michael foaf_surname: Sauberer - foaf_Person: foaf_givenName: Johann foaf_name: Stanek, Johann foaf_surname: Stanek - foaf_Person: foaf_givenName: Stefan foaf_name: Poschner, Stefan foaf_surname: Poschner - foaf_Person: foaf_givenName: Walter foaf_name: Jäger, Walter foaf_surname: Jäger - foaf_Person: foaf_givenName: Viktoria foaf_name: Zoufal, Viktoria foaf_surname: Zoufal - foaf_Person: foaf_givenName: Gaia foaf_name: Novarino, Gaia foaf_surname: Novarino foaf_workInfoHomepage: http://www.librecat.org/personId=3E57A680-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0002-7673-7178 - foaf_Person: foaf_givenName: Nicolas foaf_name: Tournier, Nicolas foaf_surname: Tournier - foaf_Person: foaf_givenName: Martin foaf_name: Bauer, Martin foaf_surname: Bauer - foaf_Person: foaf_givenName: Thomas foaf_name: Wanek, Thomas foaf_surname: Wanek - foaf_Person: foaf_givenName: Oliver foaf_name: Langer, Oliver foaf_surname: Langer bibo_doi: 10.1021/acs.molpharmaceut.8b01217 bibo_issue: '3' bibo_volume: 16 dct_date: 2019^xs_gYear dct_identifier: - UT:000460600400031 dct_language: eng dct_publisher: American Chemical Society@ dct_title: Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib@ fabio_hasPubmedId: '30694684' ...