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Xenobiotica
the fate of foreign compounds in biological systems
Volume 38, 2008 - Issue 2
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Research Article

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

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Pages 107-129 | Received 08 Sep 2007, Accepted 10 Dec 2007, Published online: 22 Sep 2008
 

Abstract

The hypothesis tested was that ketoconazole can modulate P-glycoprotein, thereby altering cellular uptake and apparent permeability (Papp) 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 Papp 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 Papp efflux of CSA and increased the Papp 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 Papp of P-glycoprotein substrates by interacting with MDR1 protein. Epigallocatechin-3-gallate and xanthohumol modulate the transport and uptake of ketoconazole.

Notes

Notes

Part of this work was presented at the Society of Toxicology's 45th annual meeting, San Diego, CA 2006. Abstract number #1686. Fan, Y. and Rodriguez-Proteau, R. Effects of ketoconazole on multidrug resistant-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Toxicological Sciences, The Toxicologist, Volume 80, Number 1-S, March 2006.

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