Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

• Published in: Drug metabolism and disposition Vol. 37; no. 6; pp. 1251 - 1258
• Main Authors: Zhao, Rong, Raub, Thomas J., Sawada, Geri A., Kasper, Steven C., Bacon, James A., Bridges, Arlene S., Pollack, Gary M.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.06.2009; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Biological Transport - drug effects; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiology; Brain - drug effects; Brain - physiology; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Osmotic Pressure; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Rats; Substrate; ABCG2 gene; Central nervous system; Pharmacokinetics; Blood brain barrier; In vitro; Breast cancer resistance protein; Encephalon
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.108.025064

Expression of breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) has been revealed recently. To investigate comprehensively the potential role of Bcrp at the murine BBB, a chemically diverse set of model compounds (cimetidine, alfuzosin, dipyridamole, and LY2228820) was evaluated using a multiexperimental design. Bcrp1 stably transfected MDCKII cell monolayer transport studies demonstrated that each compound had affinity for Bcrp and that polarized transport by Bcrp was abolished completely by the Bcrp inhibitor chrysin. However, none of the compounds differed in brain uptake between Bcrp wild-type and knockout mice under either an in situ brain perfusion or a 24-h subcutaneous osmotic minipump continuous infusion experimental paradigm. In addition, alfuzosin and dipyridamole were shown to undergo transport by P-glycoprotein (P-gp) in an MDCKII-MDR1 cell monolayer model. Alfuzosin brain uptake was 4-fold higher in mdr1a(–/–) mice than in mdr1a(+/+) mice in in situ and in vivo studies, demonstrating for the first time that it undergoes P-gp-mediated efflux at the BBB. In contrast, P-gp had no effect on dipyridamole brain penetration in situ or in vivo. In fact, in situ BBB permeability of these solutes appeared to be primarily dependent on their lipophilicity in the absence of efflux transport, and in situ brain uptake clearance correlated with the intrinsic transcellular passive permeability from in vitro transport and cellular accumulation studies. In summary, Bcrp mediates in vitro transport of various compounds, but seems to play a minimal role at the BBB in vivo.