Ketoconazole and the modulation of multidrug resistance-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models

Abstract

The hypothesis tested was that ketoconazole can modulate P-glycoprotein, thereby altering cellular uptake and apparent permeability (P_app) of multidrug-resistant substrates, such as cyclosporin A (CSA) and digoxin, across Caco-2, MDCKII-MDR1, and MDCKII wild-type cell transport models. ³H-CSA/³H-digoxin transport experiments were performed with and without co-exposure to ketoconazole, and ³H-ketoconzole transport experiments were performed with and without co-exposure to dietary flavonoids, epigallocatechin-3-gallate, and xanthohumol. Ketoconazole (3 µM) reduced the P_app efflux of CSA and digoxin from 5.07 × 10⁻⁶ to 2.91 × 10⁻⁶ cm s⁻¹ and from 2.60 × 10⁻⁶ to 1.41 × 10⁻⁶ cm s⁻¹, respectively, in Caco-2 cells. In the MDCKII-MDR1 cells, ketoconazole reduced the P_app efflux of CSA and increased the P_app absorption of digoxin. Cellular uptake of ketoconazole in the Caco-2 cells was significantly inhibited by CSA and digoxin, whereas epigallocatechin-3-gallate and xanthohumol exhibited biphasic responses. In conclusion, ketoconazole modulates the P_app of P-glycoprotein substrates by interacting with MDR1 protein. Epigallocatechin-3-gallate and xanthohumol modulate the transport and uptake of ketoconazole.