Deng Feng, Sjöstedt Noora, Santo Mariangela, Neuvonen Mikko, Niemi Mikko, Kidron Heidi
Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Tukholmankatu 8 C, P.O. Box 20, 00014, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Haartmaninkatu 8, P.O. Box 63, 00014, Finland.
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Viikinkaari 5 E, P.O. Box 56, 00014, Finland.
Eur J Pharm Sci. 2023 Feb 1;181:106362. doi: 10.1016/j.ejps.2022.106362. Epub 2022 Dec 15.
Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette (ABC) transporter for drug disposition. Inhibition of BCRP increases the plasma concentrations of BCRP substrate drugs, which potentially could lead to adverse drug reactions. The aim of the present study was to identify BCRP inhibitors amongst a library of 232 commonly used drugs and anticancer drugs approved by the United States Food and Drug Administration (FDA). BCRP inhibition studies were carried out using the vesicular transport assay. We found 75 drugs that reduced the relative transport activity of BCRP to less than 25% of the vehicle control and were categorized as strong inhibitors. The concentration required for 50% inhibition (IC) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC ranged from 1.1 to 11 µM, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. According to the drug interaction guidance documents from the FDA and the European Medicines Agency (EMA), in vivo DDI studies are warranted if the theoretical intestinal luminal concentration of a drug exceeds its IC by tenfold. Here, the IC values for eight of the drugs were 100-fold lower than their theoretical intestinal luminal concentration. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.
药物相互作用（DDIs）是安全用药的一个主要关注点。乳腺癌耐药蛋白（BCRP）是一种在药物处置方面具有临床相关性的ATP结合盒（ABC）转运蛋白。抑制BCRP会增加BCRP底物药物的血浆浓度，这可能会导致药物不良反应。本研究的目的是在美国食品药品监督管理局（FDA）批准的232种常用药物和抗癌药物库中鉴定BCRP抑制剂。使用囊泡转运试验进行BCRP抑制研究。我们发现75种药物可将BCRP的相对转运活性降低至载体对照的25%以下，并被归类为强抑制剂。对13种先前对BCRP抑制作用特征不明确的强抑制剂测定了50%抑制所需的浓度（IC）。IC范围为1.1至11μM，其中维莫非尼、达比加群酯和依维莫司是最强的抑制剂。根据FDA和欧洲药品管理局（EMA）的药物相互作用指导文件，如果一种药物的理论肠腔浓度超过其IC值十倍，则有必要进行体内DDI研究。在此，其中八种药物的IC值比其理论肠腔浓度低100倍。此外，一个机制静态模型表明，维莫非尼、贝沙罗汀、达比加群酯、利福喷汀、阿瑞匹坦和依伐卡托几乎可以完全抑制肠道BCRP，使同时服用的瑞舒伐他汀的暴露量增加90%以上。因此，有必要进行临床研究以调查这些药物是否会在人体内引起BCRP介导的DDIs。
