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Suitability of In vitro Probe Substrates for Establishing BCRP-Mediated Rosuvastatin Interactions

Breast cancer resistance protein (BCRP; ABCG2) is one of the two major clinically relevant human ATP-binding cassette (ABC)-transporter proteins that efflux drugs and xenobiotics out of cells.  Due to its ubiquitous expression in intestine (apical membrane of enterocytes), BCRP is rate-determining in the absorption of low permeability substrate drugs, thereby defining exposure.  The important role that BCRP plays in drug absorption has been demonstrated clinically in pharmacogenetic studies and in observed drug-drug interactions (DDIs) with substrates such as topotecan and rosuvastatin (a common coadministered medication), where removal of BCRP function results in exaggerated systemic exposure. Indeed, this has been identified as one of the key mechanisms behind rosuvastatin DDI where an up to 2-fold increase in exposure is observed if co-administered with a BCRP inhibitor.  To understand the risk of DDI, the regulatory authorities suggest that transporter interactions (including BCRP inhibition) should be evaluated in vitro.

To perform in vitro inhibition studies, a well-validated (and ideally clinically relevant) probe substrate is chosen to establish the interaction potential of investigational drugs.  In the case of BCRP, estrone 3-sulfate (E3S) is a well-established literature probe substrate for BCRP.  In order to understand the relevance of this probe substrate to BCRP-mediated rosuvastatin DDIs, and therefore its potential to be a surrogate for rosuvastatin in vitro, BCRP inhibitory potential in Caco-2 cells was compared using rosuvastatin or E3S as probe substrate for five drugs demonstrated to perpetrate clinical DDIs with rosuvastatin. The results from the study demonstrate both compatibility with literature IC50 values for the five drugs and good concordance for predicting BCRP DDI potential between E3S and rosuvastatin as probe substrates.  Consequently, E3S could be used as a surrogate in vitro probe substrate for rosuvastatin when assessing BCRP inhibition liability.

This research was presented at the 14th European ISSX meeting in Cologne from June 26-29, 2017.

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