Lee Caroline A, O'Connor Meeghan A, Ritchie Tasha K, Galetin Aleksandra, Cook Jack A, Ragueneau-Majlessi Isabelle, Ellens Harma, Feng Bo, Taub Mitchell E, Paine Mary F, Polli Joseph W, Ware Joseph A, Zamek-Gliszczynski Maciej J
Drug Metabolism and Pharmacokinetics, QPS LLC, Research Triangle Park, North Carolina (C.A.L.); Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (M.A.O., M.E.T.); Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.); Pharmacokinetics and Drug Metabolism (B.F.) and Clinical Pharmacology, Global Innovative Pharma Business (J.A.C.), Pfizer Inc., Groton, Connecticut; School of Pharmacy, University of Washington, Seattle, Washington (I.R.-M., T.K.R.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (M.J.Z.-G., J.W.P.) and King of Prussia, Pennsylvania (H.E.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Clinical Pharmacology, Genentech, South San Francisco, California (J.A.W.).
Drug Metabolism and Pharmacokinetics, QPS LLC, Research Triangle Park, North Carolina (C.A.L.); Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (M.A.O., M.E.T.); Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, United Kingdom (A.G.); Pharmacokinetics and Drug Metabolism (B.F.) and Clinical Pharmacology, Global Innovative Pharma Business (J.A.C.), Pfizer Inc., Groton, Connecticut; School of Pharmacy, University of Washington, Seattle, Washington (I.R.-M., T.K.R.); Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina (M.J.Z.-G., J.W.P.) and King of Prussia, Pennsylvania (H.E.); College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.); and Clinical Pharmacology, Genentech, South San Francisco, California (J.A.W.)
Drug Metab Dispos. 2015 Apr;43(4):490-509. doi: 10.1124/dmd.114.062174. Epub 2015 Jan 13.
Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.
乳腺癌耐药蛋白（BCRP；ABCG2）限制低渗透性底物药物的肠道吸收，并介导药物及代谢产物的胆汁排泄。基于BCRP介导的药物相互作用（DDIs）的临床证据以及影响药物疗效和安全性的c.421C>A功能多态性，美国食品药品监督管理局和欧洲药品管理局均建议进行临床前评估，并在适当时对BCRP介导的DDIs进行临床评估。尽管在体外已鉴定出许多BCRP底物和抑制剂，但临床转化因与其他转运体和代谢酶的重叠而受到困扰。由于在最有效和特异的人BCRP底物和抑制剂的选择以及最佳研究设计方面缺乏共识，BCRP介导的临床DDI研究的监管建议具有挑战性。本综述在对现有数据进行全面分析的基础上提出了一条前进的道路。口服柳氮磺胺吡啶（1000mg，速释片）是肠道BCRP目前最佳的临床可用底物，口服瑞舒伐他汀（20mg）是肠道和肝脏BCRP的最佳可用底物，静脉注射瑞舒伐他汀（4mg）是肝脏BCRP的最佳可用底物。口服姜黄素（2000mg）和拉帕替尼（250mg）是目前最佳的临床BCRP抑制剂。为探究临床BCRP DDI的最坏情况，建议研究对象携带BCRP c.421C/C参考基因型。此外，如果选择柳氮磺胺吡啶作为底物，建议选择快速乙酰化表型的受试者。对于瑞舒伐他汀，建议选择有机阴离子转运多肽1B1 c.521T/T基因型的受试者，并在基线期和DDI期监测瑞舒伐他汀的降胆固醇效果。一个合作联盟正在计划一项概念验证临床研究，以评估所提议的BCRP DDI研究设计。
