Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model
Shannon Dallas1, Laurent Salphati2, David Gomez-Zepeda1
1DMPK and Bioanalytical Research, Abbvie Deutschland GmbH & Co. KG, Ludwigshafen, Germany (M.M., C.H., L.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA (L.S., J.P., X.Z.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (L.C., C.A., E.P.); Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria (T.W., O.L.); Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (O.L.), Preclinical Development and Safety, Janssen Research and Development, LLC, Spring House, PA (S.D., J.K., K.D., D.S.). Merck Sharp and Dohme Corporation, Whitehouse Station, New Jersey (X.C., T.P., J.Y.); Université Paris Descartes, UMR-S 1144, Paris, France (D.G.-Z., M.-C.M., S.C., X.D.); Taconic Biosciences GmbH, Koeln, Germany (A.R., N.S.).
Abstract:
Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp(-/-)) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murineBcrppromoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.
