The goal of this dissertation is to investigate the interaction between
cimetidine and dietary flavonoids using the Caco-2 cell transport model. It has been
shown that flavonoids can change the bioavailability of pharmaceuticals, either by
inhibiting metabolizing enzymes or inhibiting the drug efflux transporters.
However, the effect of dietary flavonoids in the absorption of cimetidine has not
been investigated. Therefore, the hypothesis of this study is that the absorption of
cimetidine is mediated by a drug efflux pump, P-glycoprotein, of which dietary
flavonoids can enhance the permeability of cimetidine by reducing P-glycoprotein
function. The increase in permeability of cimetidine can increase the bioavailability
of cimetidine. To test the hypothesis, three objectives were proposed. The first
objective was to validate the Caco-2 transport model in our laboratory. The
validation was performed by measuring the electrical resistance ofthe monolayer
and determining the transport of paracellular marker. Also P-glycoprotein function
was determined using rhodamine 123.
The second objective was to describe the transport characteristics of
cimetidine in the Caco-2 cell monolayers. The permeability of cimetidine was
determined at different pH environments. When the permeability of cimetidine
from apical to basolateral and basolateral to apical was compared, there appeared to
be an effiux mechanism involved transport of cimetidine. The permeability of
cimetidine in the presence of verapamil, a P-glycoprotein competitive inhibitor,
suggested that P-glycoprotein was involved in the effiux.
The third objective was to study the effect of dietary flavonoids on the
permeability of cimetidine in the Caco-2 cell model. In the present study, four
different flavonoids, quercetin, genistein, naringenin, and xanthohumol were
selected. When co-treated with flavonoid aglycones, the permeability ofcimetidine
was significantly reduced in the basolateral to apical direction. However, only
genistin, a glycoside of genistein, significantly reduced the efflux of cimetidine.
The present studies demonstrate that some dietary flavonoids, especially
aglycones, can significantly reduce the effiux of cimetidine in the Caco-2 cell
monolayers. Therefore, the fiavonoids consumed in a normal diet have the potential
to enhance the bioavailability of cimetidine and possibly other P-glycoprotein
substrates by altering their permeability. / Graduation date: 2004
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/29868 |
| Date | 23 July 2003 |
| Creators | Taur, Jan-Shiang |
| Contributors | Rodriguez, Rosita J. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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