Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 156, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejps.2020.105593
Keywords
BCRP; ABCG2; HEK293-BCRP; vesicular transport; substrate-dependent inhibition
Categories
Funding
- [GINOP-2.2.1-15-2016-00009]
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BCRP/ABCG2 is a key factor in the pharmacokinetics of substrate drugs. Membranes from different expression systems show variation in substrate correlation and dynamic range, but good consistency in IC50 values.
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. K-m values for three substrates - estrone-3-sulfate, sulfasalazine, topotecan - correlated well between the four expression systems. In contrast, a 10-20-fold range in V-max 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.
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