The opportunity for drug-dietary interaction is an everyday occurrence whether the interaction is with food, juice, or dietary supplements. Moreover, the consumption of flavonoids is being urged because of their multiple health benefits; thus, understanding the possible biological effects of the flavonoids on intestinal drug absorption is essential. Flavonoids may be a particularly important class of modulators due to their ubiquitous occurrence in foods and drinks of plant origin and their known interactions with P-glycoprotein (Pgp) and cytochrome P450 (CYP). These dietary constituents may modulate transport in the intestinal tract and significantly alter the absorption of important therapeutic agents. The increased systemic bioavailability of some drugs, nifedipine and felodipine, associated with ingestion of grapefruit juice represents a couple of widely publicized drug-dietary-interactions. An increase or decrease in drug absorption may be due to (i) alterations in Pgp mediated or non Pgp mediated transport and/or (ii) presystemic intestinal metabolism by CYP and/or the flavin-containing monooxygenases. Furthermore, patents have been filed which incorporate flavonoids as excipients in pharmaceutical formations with the intent to alter drug absorption. Thus, the specific hypothesis of this study is that dietary flavonoids can alter the Pgp-dependent or Pgp-independent transport of certain therapeutic drugs. Studies will be conducted using flavonoids belonging to different subclasses such as isoflavone, flavanone, flavonol, and flavanol (e.g., genistein, naringenin, quercetin, and epigallocatechin gallate, respectively) to gain an insight into structure-activity relationships in the alteration of transport of Pgp-dependent substrates and Pgp-independent substrates by these phytochemicals. The flavonoids will be evaluated using Caco-2 cells, a human intestinal cell line. These cells have been well characterized to express Pgp transporters and non Pgp transporters such as Na+/K+, Na+/H+, amino acids, peptides, bile acid, and vitamin B12. This project will provide new knowledge on how flavonoids affect the dynamic transport mechanisms located in the intestinal mucosa. Thus, the results of this study will increase our understanding of the role of flavonoids found in tea, vegetables, soy, and dietary supplements in the intestinal absorption of therapeutic drugs.
| Fan, Y; Rodriguez-Proteau, R (2008) Ketoconazole and the modulation of multidrug resistance-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models. Xenobiotica 38:107-29 |
| Taur, J-S; Rodriguez-Proteau, R (2008) Effects of dietary flavonoids on the transport of cimetidine via P-glycoprotein and cationic transporters in Caco-2 and LLC-PK1 cell models. Xenobiotica 38:1536-50 |
| Rodriguez-Proteau, R; Mata, J E; Miranda, C L et al. (2006) Plant polyphenols and multidrug resistance: effects of dietary flavonoids on drug transporters in Caco-2 and MDCKII-MDR1 cell transport models. Xenobiotica 36:41-58 |
