RAPID COMMUNICATIONSBreast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probeUrquhart, Bradley L.a; Ware, Joseph A.d; Tirona, Rommel G.a c; Ho, Richard H.e; Leake, Brenda F.e; Schwarz, Ute I.a c; Zaher, Hanid; Palandra, Joed; Gregor, Jamie C.b; Dresser, George K.a; Kim, Richard B.a cAuthor Information aDivision of Clinical Pharmacology bDivision of Gastroenterology, Department of Medicine cDepartment of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada dPfizer Global Research and Development, Ann Arbor, Michigan eDepartment of Pediatrics and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Correspondence to Richard B. Kim, Room ALL-152, London Health Sciences Centre – University Campus, 339 Windermere Road, London, Ontario, N6A 5A5, Canada Tel: +519 663 3553; fax: +519 663 3232; e-mail: [email protected] Received 6 November 2007 Accepted 22 January 2008 Pharmacogenetics and Genomics: May 2008 - Volume 18 - Issue 5 - p 439-448 doi: 10.1097/FPC.0b013e3282f974dc Buy Metrics Abstract Breast cancer resistance protein (BCRP) is an efflux transporter expressed in tissues that act as barriers to drug entry. Given that single nucleotide polymorphisms (SNPs) in the ABCG2 gene encoding BCRP are common, the possibility exists that these genetic variants may be a determinant of interindividual variability in drug response. The objective of this study is to confirm the human BCRP-mediated transport of sulfasalazine in vitro, evaluate interindividual variation in BCRP expression in human intestine and to determine the role of ABCG2 SNPs to drug disposition in healthy patients using sulfasalazine as a novel in vivo probe. To evaluate these objectives, pinch biopsies were obtained from 18 patients undergoing esophagogastro–duodenoscopy or colonoscopy for determination of BCRP expression in relation to genotype. Wild-type and variant BCRP were expressed in a heterologous expression system to evaluate the effect of SNPs on cell-surface trafficking. A total of 17 healthy individuals participated in a clinical investigation to determine the effect of BCRP SNPs on sulfasalazine pharmacokinetics. In vitro, the cell surface protein expression of the common BCRP 421 C>A variant was reduced in comparison with the wild-type control. Intestinal biopsy samples revealed that BCRP protein and mRNA expression did not significantly differ between patients with 34GG/421CC versus patients with 34GG/421CA genotypes. Remarkably, in subjects with 34GG/421CA genotype, sulfasalazine area under the concentration–time curve was 2.4-fold greater compared with 34GG/421CC subjects (P<0.05). This study links commonly occurring SNPs in BCRP with significantly increased oral sulfasalazine plasma exposure in humans. Accordingly, sulfasalazine may prove to have utility as in vivo probe for assessing the clinical impact of BCRP for the disposition and efficacy of drugs. © 2008 Lippincott Williams & Wilkins, Inc.