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

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Y Fan, R Rodriguez-Proteau

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. (3)H-CSA/(3)H-digoxin transport experiments were performed with and without co-exposure to ketoconazole, and (3)H-ketoconzole transport experiments were performed with and without co-exposure to dietary flavonoids, epigallocatechin-3-gallate, and xanthohumol. Ketoconazole (3 microM) reduced the P(app) efflux of CSA and digoxin from 5.07 x 10(-6) to 2.91 x 10(-6) cm s(-1) and from 2.60 x 10(-6) to 1.41 x 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.

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Citations

Oct 21, 2011·Pharmaceutical Research·Ken-ichi Umehara, Gian Camenisch
Jun 24, 2011·Journal of Pharmaceutical Sciences·Dalia A Hamdy, Dion R Brocks
Nov 10, 2010·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Dalia A Hamdy, Dion R Brocks
Nov 30, 2015·Analytical and Bioanalytical Chemistry·Lucie ZelenáPetr Solich
May 7, 2010·Journal of Veterinary Pharmacology and Therapeutics·B KuKanich, M Hubin
Oct 5, 2016·Journal of Agricultural and Food Chemistry·Michael DreselThomas Hofmann
Jan 13, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ming LiuJinlai Miao
Jul 21, 2017·Scientific Reports·Priyambada ParhiSanjeeb Kumar Sahoo
Jul 16, 2019·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Yulin WangThomas Efferth
Feb 25, 2021·Biopharmaceutics & Drug Disposition·Jonathan J NovakLi Di

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