BCRP Inhibition

BCRP inhibition is in our portfolio of in vitro  drug transporter services. Cyprotex delivers consistent, high quality data in line with our published transporter strategy review, for either your early stage screening projects or your later stage regulatory studies according to FDA, EMA, PMDA and ICH guidance.

The impact of BCRP inhibition and its measurement in vitro:

• BCRP (Breast Cancer Resistance Protein/ABCG2) is expressed in many tissues including the gastrointestinal tract, liver, kidney and brain endothelium¹.
• Inhibition of intestinal BCRP has shown to be responsible for several clinical drug-drug interactions involving specific statin common co-medications such as rosuvastatin and atorvastatin, resulting in their increased absorption and subsequent exposure (up to 2 fold increase in AUC)^2,3.
• The International Transporter Consortium¹, the FDA guidance⁴ and the EMA guidance⁵ recommend investigating inhibition of BCRP due to BCRP's clinical importance in the absorption and disposition of substrate drugs.
• Cyprotex uses polarized Caco-2 cell monolayers (the “gold-standard” methodology) to identify BCRP inhibitors using a range of test inhibitor concentrations in the presence of the probe substrate estrone-3-sulfate, a good surrogate for the clinically relevant BCRP substrate rosuvastatin. This method conforms with the recommended methods within the International Transporter Consortium white paper¹, the FDA interactions guidance⁴ and the EMA drug interactions guideline⁵.
• However, if a test compound has inherently low passive permeability, then BCRP-expressing inside-out membrane vesicles can be used as an alternate in vitro test system to identify BCRP inhibitors and reduce the potential risk of false negatives from the polarized cell monolayer system for such compounds.

A set of known BCRP inhibitors were investigated in Cyprotex's Cellular BCRP Inhibition assay using estrone-3-sulfate as substrate.

A set of known BCRP inhibitors were investigated in Cyprotex's Vesicle BCRP inhibition assay using estrone-3-sulfate as substrate.

_{1) The International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Disc 9(3); 215–236
2) Elsby R et al., (2012) Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: It's not just about OATP1B1. Clinical Pharmacology & Therapeutics 92(5); 584-598
3) Elsby R et al., (2016) Solitary inhibition of the Breast Cancer Resistance Protein efflux transporter results in a clinically significant drug-drug interaction with rosuvastatin by causing up to a 2-fold increase in statin exposure. Drug Metab Dispos 44(3); 398-408
4) FDA Guidance for Industry – In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020)
5) The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (Adopted 2012)
6) Jones H et al., (2017) Estrone 3-sulfate as a surrogate Breast Cancer Resistance Protein (BCRP) in vitro probe substrate for assessing drug-drug interaction risk with rosuvastatin (ISSX published abstract/poster)}