PT  - JOURNAL ARTICLE
AU  - Agnes Poirier
AU  - Renee Portmann
AU  - Anne-Christine Cascais
AU  - Urs Bader
AU  - Isabelle Walter
AU  - Mohammed Ullah
AU  - Christoph Funk
TI  - The Need for BCRP Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When and How?
AID  - 10.1124/dmd.114.058248
DP  - 2014 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.114.058248
4099  - http://dmd.aspetjournals.org/content/early/2014/07/02/dmd.114.058248.short
4100  - http://dmd.aspetjournals.org/content/early/2014/07/02/dmd.114.058248.full
AB  - Whilst the multiplicity in transport proteins assessed during drug development is continuously increasing, the clinical relevance of the Breast Cancer Resistance Protein (BCRP, MXR) is still under debate. Our aim here is to rationalize the need to consider BCRP substrate and inhibitor interactions and to define optimum selection and acceptance criteria between cell-based and vesicle-based assays in vitro. Information on the preclinical and clinical pharmacokinetics (PK), drug-drug interactions and pharmacogenomics data were collated for 13 marketed drugs whose PK is reportedly associated with BCRP interaction. Clinical examples where BCRP impacts drug PK and efficacy appear to be rare and confounded by interactions with other transporters. Thirty-seven compounds were selected to be tested as BCRP substrates in a MDCKII cell-based assay and 18 in vesicles. Depending on the physico-chemical compound properties, we observe both in vitro systems to give false-negative read-outs. In addition, the inhibition potential of 19 compounds against BCRP was assessed in vesicles and in MDCKII cells, where we observed significant system and substrate-dependent IC50 values. Neither of the two test systems is therefore superior to each other. Instead, one system may offer advantages under certain situations (e.g. low permeability) and thus should be selected based on the physico-chemical compound properties. Finally, given the clinical relevance of BCRP, we propose that its evaluation should remain issue-driven: for low permeable, low bioavailable drugs, in particular when other more common processes do not allow a mechanistic understanding of any unexpected absorption or brain disposition, and for drugs with a low therapeutic window.