Abstract
Tariquidar was developed as a specific inhibitor of the efflux transporter ABCB1. Recent positron emission tomographic brain imaging studies using [(11)C]tariquidar to measure ABCB1 (P-gp, P-glycoprotein) density in mice indicate that the inhibitor may not be as specific as previously thought. We examined its selectivity as an inhibitor and a substrate for the human transporters P-gp, breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance protein 1 (MRP1, ABCC1). Our results show that at low concentrations, tariquidar acts selectively as an inhibitor of P-gp and also as a substrate of BCRP. At much higher concentrations (≥100 nM), tariquidar acts as an inhibitor of both P-gp and BCRP. Thus, the in vivo specificity of tariquidar depends on concentration and the relative density and capacity of P-gp vs BCRP.
Keywords:
P-glycoprotein; Positron emission tomography; blood−brain barrier; breast cancer resistance protein; drug transporters; tariquidar; transport inhibitors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors*
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ATP-Binding Cassette Transporters / metabolism
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Multiple / physiology
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Female
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HEK293 Cells
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Humans
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Quinolines / chemistry
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Quinolines / metabolism
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Quinolines / pharmacology*
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Substrate Specificity / drug effects
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Neoplasm Proteins
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Quinolines
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tariquidar