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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design
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Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

机译：临床药代动力学和药物相互作用中的乳腺癌抗性蛋白（ABCG2）：临床受害者和作案者药物相互作用研究设计的实用建议

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摘要

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.
机译：乳腺癌抗性蛋白（BCRP; ABCG2）限制低渗透性底物药物的肠道吸收，并介导药物和代谢物的胆汁排泄。根据BCRP介导的药物相互作用（DDI）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，并在适当时进行临床评估BCRP介导的DDI评估。尽管已在体外鉴定出许多BCRP底物和抑制剂，但由于与其他转运蛋白和代谢酶的重叠，临床翻译受到了混淆。 BCRP介导的临床DDI研究的监管建议颇具挑战性，因为在选择最健壮和最特异的人BCRP底物和抑制剂以及最佳研究设计方面尚无共识。这篇综述基于对可用数据的全面分析，提出了一条前进的道路。口服柳氮磺吡啶嗪（1000 mg，速释片）是肠BCRP的最佳临床底物，口服瑞舒伐他汀（20 mg）用于肠和肝BCRP，静脉注射瑞舒伐他汀（4 mg）用于肝BCRP。口服姜黄素（2000毫克）和拉帕替尼（250毫克）是目前临床上最好的BCRP抑制剂。为了询问最坏情况的临床BCRP DDI情况，建议携带BCRP c.421C / C参考基因型的研究对象。另外，如果选择柳氮磺胺吡啶作为底物，则推荐具有快速乙酰化表型的受试者。对于瑞舒伐他汀，推荐具有有机阴离子转运多肽1B1 c.521T / T基因型的受试者，并监测瑞舒伐他汀在基线和DDI阶段的降胆固醇作用。一个合作联盟正在计划进行概念验证性临床研究，以评估建议的BCRP DDI研究设计。

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