Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier
- 9 March 2009
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 37 (6), 1251-1258
- https://doi.org/10.1124/dmd.108.025064
Abstract
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.Keywords
This publication has 43 references indexed in Scilit:
- P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of TopotecanClinical Cancer Research, 2007
- Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapyThe Pharmacogenomics Journal, 2007
- Influence of breast cancer resistance protein (Abcg2) and p‐glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood–brain barrierJournal of Neurochemistry, 2007
- Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free FractionJournal of Pharmacology and Experimental Therapeutics, 2007
- Expression of drug transporters at the blood–brain barrier using an optimized isolated rat brain microvessel strategyBrain Research, 2007
- Multidrug Resistance Protein 4 Protects Bone Marrow, Thymus, Spleen, and Intestine from Nucleotide Analogue–Induced DamageCancer Research, 2007
- Localization of Breast Cancer Resistance Protein (BCRP) in Microvessel Endothelium of Human Control and Epileptic BrainEpilepsia, 2005
- Investigation of Efflux Transport of Dehydroepiandrosterone Sulfate and Mitoxantrone at the Mouse Blood-Brain Barrier: A Minor Role of Breast Cancer Resistance ProteinJournal of Pharmacology and Experimental Therapeutics, 2004
- Development of anIn SituMouse Brain Perfusion Model and its Application tomdr1aP-Glycoprotein-Deficient MiceJournal of Cerebral Blood Flow & Metabolism, 2000
- Quantitative Approaches to Delineate Passive Transport Mechanisms in Cell Culture MonolayersPublished by Informa UK Limited ,1999