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1. J Pharm Sci. 2012 Feb 22. doi: 10.1002/jps.23069. [Epub ahead of print]

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.

Mease K, Sane R, Podila L, Taub ME.

Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut.

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. © 2012 Wiley Periodicals, Inc. and the
American Pharmacists Association J Pharm Sci.

Copyright © 2012 Wiley Periodicals, Inc.

PMID: 22359351 [PubMed - as supplied by publisher]