Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: a strategy to assess the interaction of a new chemical entity with P-gp, BCRP, and MRP2.

Abstract

Determining the interaction of a molecule with membrane transporters is challenging because of overlapping substrate and inhibitor specificities and coexpression of multiple transporters. Caco-2 and MDCK-MDR1 cells were used to evaluate the selectivity of zosuquidar (LY335979), fumitremorgin C (FTC), and MK571 as inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2), respectively. Although these compounds are commonly used as transporter inhibitors, the concentrations at which they selectively inhibit P-gp, BCRP, and MRP2 have not been definitively assessed. In Caco-2 cells, which express P-gp, BCRP, and MRP2, FTC (1 µM) selectively inhibited the efflux of BCRP substrates estrone-3-sulfate and genistein; however, at 10 µM, FTC partially inhibited the efflux of P-gp substrates paclitaxel and digoxin. MK571 (50 µM), commonly used to inhibit MRP2, inhibited the efflux of P-gp and BCRP probe substrates in Caco-2 cells. In MDCK-MDR1 cells, which express human P-gp but not BCRP or MRP2, MK571 (50 µM) and FTC (10 µM) did not inhibit paclitaxel and digoxin efflux. Using Caco-2 cell monolayers, selected probe substrates, and optimized concentrations of LY335979 (3 µM) and FTC (1 µM), we propose a strategy to evaluate the interaction of a molecule with P-gp, BCRP, and MRP2.

• Authors: Kirsten Mease, Rucha Sane, Lalitha Podila, Mitchell E Taub
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 101 Issue 5 Pg. 1888-97 (May 2012) ISSN: 1520-6017 [Electronic] United States
• PMID: 22359351 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• ABCC2 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Vinblastine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Caco-2 Cells
• Dogs
• Humans
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• Vinblastine (metabolism)