| アブストラクト | Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter involved in clinically relevant drug-drug interactions. We aimed to identify new BCRP inhibitors among drugs used in cancer treatment. Accordingly, 133 drugs were screened at 50 microM for inhibition of BCRP using vesicular transport assay. Half-maximal inhibitory concentrations (IC(50)) were predicted, and compounds showing the highest inhibitory potencies relative to their systemic (I(1)) or intestinal (I(2)) concentrations were selected for experimental IC(50) determination. A mechanistic static model was used to predict potential interactions with the BCRP substrate rosuvastatin in humans. Food and Drug Administration Adverse Event Reporting System (FAERS) was searched for signals of rosuvastatin-induced rhabdomyolysis during co-administration with the investigated drugs. Of the 133 drugs screened, 42 had a predicted IC(50) value over 0.1xI(1) and 61 over 10xI(2), suggesting potential inhibition in humans. IC(50) values were experimentally determined for 24 selected drugs. Cabozantinib and midostaurin were the strongest inhibitors, with IC(50) values of 0.65 and 0.69 microM, respectively. Moreover, the model suggested that midostaurin, cabozantinib, and alpelisib could almost fully inhibit intestinal BCRP, nearly doubling rosuvastatin exposure (1.83- to 1.94-fold). Entrectinib, alpelisib, flutamide, abiraterone, and capecitabine were predicted to increase rosuvastatin exposure by 1.45- to 1.63-fold through BCRP inhibition. FAERS analysis indicated a higher frequency of rhabdomyolysis reports when abiraterone was co-administered with rosuvastatin compared with all reports without abiraterone, with a reporting odds ratio of 17.3. This study identified multiple previously unrecognized BCRP inhibitors, highlighting the potential for clinically relevant BCRP‑mediated drug-drug interactions in oncology patients. |
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| 組織名 | Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki,;Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of;Medicine, University of Helsinki, Helsinki, Finland.;Medicine, University of Helsinki, Helsinki, Finland; Pharmaceutical Sciences;Laboratory, Department of Natural and Health Sciences, the Faculty of Science and;Engineering, Abo Akademi University, Turku, Finland.;Medicine, University of Helsinki, Helsinki, Finland; Integrative Physiology and;Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.;Integrative Physiology and Pharmacology, Institute of Biomedicine, University of;Turku, Turku, Finland; Unit of Clinical Pharmacology, Turku University Hospital,;Turku, Finland.;Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical;Pharmacology, HUS Diagnostic Center, Helsinki University, Hospital, Helsinki,;Finland. Electronic address: mikko.niemi@helsinki.fi.;Finland. |
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