title: The need for human breast cancer resistance protein substrate and inhibition evaluation in drug discovery and development: why, when, and how?
abstract: Although the multiplicity in transport proteins assessed during drug development is continuously increasing, the clinical relevance of the breast cancer resistance protein (BCRP) is still under debate. Here, our aim 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 was 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 cell-based assay using MDCKII cells (Madin-Darby canine kidney cells) and 18 in membrane vesicles. Depending on the physicochemical compound properties, we observed both in vitro systems to give false-negative readouts. 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. Therefore, neither of the two test systems is superior to the other. Instead, one system may offer advantages under certain situations (e.g., low permeability) and thus should be selected based on the physicochemical 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.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Agnès
authors.initials: A
authors.lastname: Poirier
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Renée
authors.initials: R
authors.lastname: Portmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Cascais
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Bader
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Walter
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ullah
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland christoph.funk@roche.com.
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs; D055808:Drug Discovery / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D018374:LLC-PK1 Cells; D061985:Madin Darby Canine Kidney Cells; D026901:Membrane Transport Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013552:Swine
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations