The "specific" P-glycoprotein inhibitor Tariquidar is also a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2)

ACS Chem Neurosci. 2011 Feb 16;2(2):82-9. doi: 10.1021/cn100078a. Epub 2010 Oct 21.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Multiple / physiology
  • Female
  • HEK293 Cells
  • Humans
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology*
  • Substrate Specificity / drug effects

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Neoplasm Proteins
  • Quinolines
  • tariquidar