Alterations in the permeability of cimetidine by dietary flavonoids using an in vitro transport model, Caco-2 cell

Graduation date: 2004The goal of this dissertation is to investigate the interaction between\ud cimetidine and dietary flavonoids using the Caco-2 cell transport model. It has been\ud shown that flavonoids can change the bioavailability of pharmaceuticals, either by\ud inhibiting metabolizing enzymes or inhibiting the drug efflux transporters.\ud However, the effect of dietary flavonoids in the absorption of cimetidine has not\ud been investigated. Therefore, the hypothesis of this study is that the absorption of\ud cimetidine is mediated by a drug efflux pump, P-glycoprotein, of which dietary\ud flavonoids can enhance the permeability of cimetidine by reducing P-glycoprotein\ud function. The increase in permeability of cimetidine can increase the bioavailability\ud of cimetidine. To test the hypothesis, three objectives were proposed. The first\ud objective was to validate the Caco-2 transport model in our laboratory. The\ud validation was performed by measuring the electrical resistance ofthe monolayer\ud and determining the transport of paracellular marker. Also P-glycoprotein function\ud was determined using rhodamine 123.\ud The second objective was to describe the transport characteristics of\ud cimetidine in the Caco-2 cell monolayers. The permeability of cimetidine was\ud determined at different pH environments. When the permeability of cimetidine\ud from apical to basolateral and basolateral to apical was compared, there appeared to\ud be an effiux mechanism involved transport of cimetidine. The permeability of\ud cimetidine in the presence of verapamil, a P-glycoprotein competitive inhibitor,\ud suggested that P-glycoprotein was involved in the effiux.\ud The third objective was to study the effect of dietary flavonoids on the\ud permeability of cimetidine in the Caco-2 cell model. In the present study, four\ud different flavonoids, quercetin, genistein, naringenin, and xanthohumol were\ud selected. When co-treated with flavonoid aglycones, the permeability ofcimetidine\ud was significantly reduced in the basolateral to apical direction. However, only\ud genistin, a glycoside of genistein, significantly reduced the efflux of cimetidine.\ud The present studies demonstrate that some dietary flavonoids, especially\ud aglycones, can significantly reduce the effiux of cimetidine in the Caco-2 cell\ud monolayers. Therefore, the fiavonoids consumed in a normal diet have the potential\ud to enhance the bioavailability of cimetidine and possibly other P-glycoprotein\ud substrates by altering their permeability