Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

• Published in: European journal of pharmaceutical sciences 2023-02, Vol.181, p.106362, Article 106362
• Main Authors: Deng, Feng, Sjöstedt, Noora, Santo, Mariangela, Neuvonen, Mikko, Niemi, Mikko, Kidron, Heidi
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; ATP-Binding Cassette Transporters - metabolism; BCRP; Biological Transport; Breast Neoplasms; Dabigatran; Drug interaction; Drug Interactions; Female; Humans; Inhibition; Mechanistic static model; Neoplasm Proteins - metabolism; Pharmaceutical Preparations; Rosuvastatin; Vemurafenib; Vesicular transport assay
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2022.106362

•Inhibition of BCRP may enhance the absorption of its substrates (e.g. rosuvastatin).•Here, we identified novel inhibitors of BCRP among 232 marketed drugs.•Several drugs were predicted to increase rosuvastatin exposure markedly. 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 (IC50) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC50 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 IC50 by tenfold. Here, the IC50 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. [Display omitted]