Effects of dietary flavonoids on the transport of cimetidine via P-glycoprotein and cationic transporters in Caco-2 and LLC-PK1 cell models
- 21 November 2008
- journal article
- research article
- Published by Taylor & Francis Ltd in Xenobiotica
- Vol. 38 (12), 1536-1550
- https://doi.org/10.1080/00498250802499467
Abstract
1. The hypotheses tested were to study cimetidine as a substrate of P-glycoprotein (P-gp) and organic cation transport systems and the modulatory effects of eight flavonoid aglycones and glycosides on these transport systems using Caco-2 and LLC-PK1 cells. 2. Transport and uptake experiments of (20 µM) 3H-cimetidine were performed with and without co-exposure to quercetin, quercetrin, rutin, naringenin, naringin, genistein, genistin, and xanthohumol. Co-treatment decreased basolateral to apical (B to A) permeability (Papp) of cimetidine from 2.02 to 1.24 (quercetin), 1.06 (naringenin), 1.24 (genistein), and 0.96 (xanthohumol) × 10−6 cm s−1 in Caco-2 cells and from 10.76 to 1.65 (quercetin), 2.05 (naringenin), 2.88 (genistein), and 1.95 (xanthohumol) × 10−6 cm s−1 in LLC-PK1 cells. Genistin significantly reduced B to A Papp of cimetidine to 1.24 × 10−6 cm s−1 in Caco-2 cells. Basolateral intracellular uptake rate of cimetidine was enhanced 145–295% when co-treated with flavonoids. Co-treatment with P-glycoprotein and organic cation transporter inhibitors, verapamil and phenoxybenzamine, resulted in reduced B to A permeability and slower basolateral intracellular uptake rate of cimetidine. Intracellular uptake rate of 14C-tetraethylammonium (TEA) was reduced in the presence of quercetin, naringenin and genistein in LLC-PK1 cells. 3. In conclusion, quercetin, naringenin, genistein, and xanthohumol reduced P-gp-mediated transport and increased the basolateral uptake rate of cimetidine. Quercetin, naringenin, genistein, but not xanthohumol, reduced intracellular uptake rate of TEA in LLC-PK1 cells. These results suggest that flavonoids may have potential to alter the disposition profile of cimetidine and possibly other therapeutics that are mediated by P-gp and/or cation transport systems.Keywords
This publication has 29 references indexed in Scilit:
- Interaction of Flavonoids and Intestinal Facilitated Glucose TransportersPlanta Medica, 2007
- Comparative assessment of endocrine modulators with oestrogenic activity: I. Definition of a hygiene-based margin of safety (HBMOS) for xeno-oestrogens against the background of European developmentsArchives of Toxicology, 2001
- Comparative Studies on in Vitro Methods for Evaluating in Vivo Function of MDR1 P-GlycoproteinPharmaceutical Research, 2001
- Flavonoid-Related Modulators of Multidrug Resistance: Synthesis, Pharmacological Activity, and Structure−Activity RelationshipsJournal of Medicinal Chemistry, 1999
- Absorption, metabolism and health effects of dietary flavonoids in manBiomedicine & Pharmacotherapy, 1997
- Primary Structure and Functional Expression of the Apical Organic Cation Transporter from Kidney Epithelial LLC-PK1CellsOnline Journal of Public Health Informatics, 1997
- Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoproteinBiochemical Pharmacology, 1997
- Comparison of HT29-18-C1 and Caco-2 Cell Lines as Models for Studying Intestinal Paracellular Drug AbsorptionPharmaceutical Research, 1996
- Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivativesBiochemical Journal, 1992
- Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activityPharmacological Research Communications, 1985