The Impact of Breast Cancer Resistance Protein (BCRP/ABCG2) on Drug Transport Across Caco-2 Cell Monolayers
| Autor: | Iichiro Kawahara, Takuya Fujita, Satoyo Nishikawa, Akira Yamamoto, Yusuke Kono |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Abcg2
Estrone Cell Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Irinotecan 030226 pharmacology & pharmacy Permeability 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ciprofloxacin medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Intestinal Mucosa Intestinal permeability biology Chemistry Daidzein Apical membrane medicine.disease In vitro Neoplasm Proteins Sulfasalazine medicine.anatomical_structure Nitrofurantoin Caco-2 030220 oncology & carcinogenesis biology.protein Feasibility Studies Efflux Caco-2 Cells Topotecan |
| Zdroj: | Drug Metabolism and Disposition. 48:491-498 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | Breast cancer resistance protein (BCRP) is expressed on the apical membrane of small intestinal epithelial cells and functions as an efflux pump with broad substrate recognition. Therefore, quantitative evaluation of the contribution of BCRP to the intestinal permeability of new chemical entities is very important in drug research and development. In this study, we assessed the BCRP-mediated efflux of several model drugs in Caco-2 cells using WK-X-34 as a dual inhibitor of P-glycoprotein (P-gp) and BCRP and LY335979 as a selective inhibitor of P-gp. The permeability of daidzein was high with an apparent permeability coefficient for apical-to-basal transport (PAB) of 20.3 × 10−6 cm/s. In addition, its efflux ratio (ER) was 1.55, indicating that the contribution of BCRP to its transport is minimal. Estrone-3-sulfate and ciprofloxacin showed relatively higher ER values (>2.0), whereas their BCRP-related absorptive quotient (AQBCRP) was 0.21 and 0.3, respectively. These results indicate that BCRP does not play a major role in regulating the permeability of estrone-3-sulfate and ciprofloxacin in Caco-2 cells. Nitrofurantoin showed a PAB of 1.8 × 10−6 cm/s, and its ER was 7.6. However, the AQBCRP was 0.37, suggesting minimal contribution of BCRP to nitrofurantoin transport in Caco-2 cells. In contrast, topotecan, SN-38, and sulfasalazine had low PAB values (0.81, 1.13, and 0.19 × 10−6 cm/s, respectively), and each AQBCRP was above 0.6, indicating that BCRP significantly contributes to the transport of these compounds in Caco-2 cells. In conclusion, Caco-2 cells are useful to accurately estimate the contribution of BCRP to intestinal drug absorption. SIGNIFICANCE STATEMENT We performed an in vitro assessment of the contribution of breast cancer resistance protein (BCRP) to the transport of BCRP and/or P-glycoprotein (P-gp) substrates across Caco-2 cell monolayers using absorptive quotient, which has been proposed to represent the contribution of drug efflux transporters to the net efflux. The present study demonstrates that the combined use of a BCRP/P-gp dual inhibitor and a P-gp selective inhibitor is useful to estimate the impact of BCRP and P-gp on the permeability of tested compounds in Caco-2 cells. |
| Databáze: | OpenAIRE |
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