MRP2-mediated transport of etoposide in MDCKII MRP2 cells is unaffected by commonly used non-ionic surfactants

• Published in: International journal of pharmaceutics Vol. 565; pp. 306 - 315
• Main Authors: Nielsen, Salli, Westerhoff, Anne Marijke, Gé, Lorraine Gaenaelle, Carlsen, Krestine Lundgaard, Pedersen, Maria Diana Læssøe, Nielsen, Carsten Uhd
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.06.2019
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Biological Transport; Cyclosporine - pharmacology; Digoxin; Dogs; Efflux transporters; Etoposide; Etoposide - administration & dosage; Madin Darby Canine Kidney Cells; MDCKII MRP2 cells; MRP2; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Non-ionic surfactants; Surface-Active Agents - pharmacology; Etoposide; MRP2; Digoxin; Non-ionic surfactants; Efflux transporters; MDCKII MRP2 cells
• DOI: 10.1016/j.ijpharm.2019.05.023
• ISSN: 0378-5173

[Display omitted] The aim of the present study was to investigate the ability of non-ionic surfactants to inhibit MRP2-mediated transport in vitro in MDCKII MRP2 cells. Transport studies across MDCKII MRP2 cell monolayers were performed using 3H-etoposide and 3H-digoxin. 19 different non-ionic surfactants, including several polysorbates (PS), cremophor EL, vitamin E-TPGS, and n-nonyl β-D-glucopyranoside (NG), were investigated. Barrier function of the cells was investigated measuring TEER and transport of 14C-glycine. The amount of isotope was quantified using liquid scintillation counting. In MDCKII MRP2 cells a polarized transport of etoposide and digoxin in the secretory (basolateral to apical) direction with efflux ratios of 5.5 ± 0.7 and 18.5 ± 4.2, respectively, was measured. P-gp inhibitors such as valspodar and zosuquidar did not affect etoposide transport, and furthermore PS20 decreased secretory transport of digoxin, but not of etoposide. Transport of etoposide was therefore mainly MRP2-mediated and used as a probe to investigate pharmaceutical excipients. Non-ionic surfactants did not modulate etoposide transport across intact cell monolayers of MRP2 overexpressing MDCKII cells, although preliminary studies suggest that most were able to alter MRP2-mediated efflux of the fluorescent 5-chloromethylfluorescein (CMF). In conclusion, etoposide transport across MDCKII MRP2 cells was modulated by cyclosporin A, an inhibitor of MRP2 and P-gp, but not by specific P-gp inhibitors (valspodar and zosuquidar), which suggests that etoposide transport is primarily influenced by MRP2. In addition, commonly used non-ionic surfactants did not decrease MRP2-mediated etoposide transport in MDCKII MRP2 cells. These results suggest that etoposide transport in MDCKII MRP2 cells is a model system to investigate MRP2 interactions, and that surfactants may not have a large potential for increasing oral bioavailability of drugs through inhibition of MRP2 transport activity.