Multidrug resistance associated protein 2 (MRP2) is an important efflux transporter involved in clinical drug disposition and drug-drug interactions. The study of MRP2-mediated drug transport has become an integral part of drug discovery and development. In particular, screening of specific MRP2 inhibitors will help overcome the multidrug resistance in cancer. In this report, a new method for rapid and sensitive detection of Mrp2 function was established via using mouse small intestinal organoids. Firstly, small intestinal crypts isolated from mouse intestine were induced by Noggin, R-spondin1 and EGF to develop three-dimensional (3D) organoids. Secondly, the 3D organoids were characterized by the physical and physiological structure of Mrp2-mediated drug transport. Finally, Mrp2 fluorescent substrate 5(6)-carboxyl- 2', 7'-dichlorofluorescein (CDF) and its inhibitor MK-571 and probenecid were used to demonstrate Mrp2-mediated CDF transport in 3D organoids. The results showed that the small intestinal organoids have a physiological structure for Mrp2-mediated compound transport. Moreover, MK-571 and probenecid, inhibitors of MRP2, significantly decreased the accumulation of CDF in 3D organoids. In summary, a novel intestinal organoid model has been successfully established for the rapid and effective study of Mrp2-mediated drug transport.
Keywords: Drug transport; Intestinal organoids; Mouse; Multidrug resistance-associated protein 2 (Mrp2); Transporter model.
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