In Vitro Characterization of Intestinal Transporter, Breast Cancer Resistance Protein (BCRP)

The organ distribution and substrate specificity of breast cancer resistance protein (BCRP), the product of the human ABCG2 gene, overlaps considerably with that of P-glycoprotein. Both are up-regulated in some cancers, leading to drug resistance, and can mediate drug-drug interactions when two drugs, one a substrate and the other an inhibitor or substrate of the same transporter, are co-administered. Thus, the U.S. FDA and the EMA now require that all NCEs be evaluated as substrates and inhibitors of BCRP. This chapter will cover in vitro assays for human BCRP, including cell-based (over-expressing and knockdown cells) and subcellular (membrane vesicle) approaches; the advantages of intact cells for discerning the complex interplay among the various uptake and efflux transporters will be discussed. Only recently have cell lines become available in which human BCRP is over-expressed; the advantages and limitations of this model will be illustrated. The uses and limitations of existing pharmacologic reagents, and the importance of pairing a given probe substrate with the appropriate biological model, will be discussed and illustrated as well.