Pheophorbide A: Fluorescent Bcrp Substrate to Measure Oral Drug-Drug Interactions in Real-Time In Vivo
| Autor: | Erin G. Schuetz, Samit Ganguly, Kazuto Yasuda |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Chlorophyll
Male Abcg2 Enterocyte Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Fluorescence Cell Line Madin Darby Canine Kidney Cells 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Dogs In vivo medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Drug Interactions Mice Knockout biology Special Section – New Models in Drug Metabolism and Transport Chemistry Biological Transport In vitro medicine.anatomical_structure Pheophorbide A Cell culture 030220 oncology & carcinogenesis biology.protein Curcumin Efflux |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 46(11) |
| ISSN: | 1521-009X |
| Popis: | We investigated whether pheophorbide A (PhA) could serve as a selective breast cancer resistance protein (BCRP) substrate (victim) to screen in vivo using fluorescent live animal imaging for transporter-mediated interactions with orally administered inhibitors (perpetrators), and whether that could be coupled with serum sampling to measure the systemic concentration of PhA with a fast-throughput in vitro fluorescent assay. PhA is a breakdown product of chlorophyll and is highly fluorescent in the near-infrared (NIR) spectrum. Whole-body NIR fluorescence was greater in the Bcrp KO compared with wild-type (WT) mice fed a regular diet containing chlorophyll and PhA, with fluorescence in WT mice confined to the intestine. PhA intestinal enterocyte fluorescence, after removing lumen contents, was greater in Bcrp knockout (KO) mice versus WT mice due to PhA enterocyte absorption and lack of PhA efflux by Bcrp. This difference was eliminated by maintaining the mice on an alfalfa (chlorophyll/PhA)-free diet. The area under the fluorescence ratio-time curve up to 6 hours (AUC(FL 0–6 h)) of orally administrated PhA was 3.5 times greater in the Bcrp KO mice compared with WT mice, and the PhA serum concentration was 50-fold higher in KO mice. Pretreatment with known BCRP inhibitors lapatinib, curcumin, elacridar, pantoprazole, and sorafenib, at clinically relevant doses, significantly increased PhA AUC(FL 0–6 h) by 2.4-, 2.3-, 2.2-, 1.5-, and 1.4-fold, respectively, whereas the area under PhA serum concentration-time curve calculated up to 6 hours (AUC(Serum 0-6 h)) increased by 13.8-, 7.8-, 5.2-, 2.02-, and 1.45-fold, respectively, and corresponded to their hierarchy as in vitro BCRP inhibitors. Our results demonstrate that live animal imaging using PhA can be used to identify BCRP inhibitors and to assess the potential for BCRP-mediated clinical drug-drug interactions. |
| Databáze: | OpenAIRE |
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