09/13/2020 - Role of transporters in drug ADME

Inhibition of ABCG2/BCRP-mediated Transport-correlation Analysis of Various Expression Systems and Probe Substrates

Zsolt Sáfár 1, Gábor Kecskeméti 2, Judit Molnár 3, Anita Kurunczi 4, Zoltán Szabó 5, Tamás Janáky 6, Emese Kis 7, Péter Krajcsi 8

Affiliations expand

PMID: 33059043 DOI: 10.1016/j.ejps.2020.105593


BCRP / ABCG2 is a key determinant of pharmacokinetics of substrate drugs. Several BCRP substrates and inhibitors are of low passive permeability, and the vesicular transport assay works well in this permeability space. Membranes were prepared from BCRP-HEK293, MCF-7/MX, and baculovirus-infected Sf9 cells with (BCRP-Sf9-HAM), and without (BCRP-Sf9) cholesterol loading. Km values for three substrates - estrone-3-sulfate, sulfasalazine, topotecan - correlated well between the four expression systems. In contrast, a 10-20-fold range in Vmax values was observed, with BCRP-HEK293 membranes possessing the largest dynamic range. IC50 values of the different test systems were similar to each other, with 94.4% of pairwise comparisons being within 3-fold. Substrate dependent inhibition showed somewhat greater variation, as 81.4% of IC50 values in the BCRP-HEK293 membranes were within 3-fold in pairwise comparisons. Overall, BCRP-HEK293 membranes demonstrated the highest activity. The IC50 values showed good concordance but substrate dependent inhibition was observed for some drugs.

Keywords: ABCG2; BCRP; HEK293-BCRP; substrate-dependent inhibition; vesicular transport.

Copyright © 2020 Elsevier B.V. All rights reserved.

open_in_new Read the Source

Next: Calibrating the In Vitro-In Vivo Correlation for OATP-Mediated Drug-Drug Interactions with Rosuvastatin Using Static and PBPK Models

Previous: Pitfalls in Predicting Hepatobiliary Drug Transport Using Human Sandwich-Cultured Hepatocytes