P-glycoprotein (Pgp), which leads to multidrug resistance in tumour cells,
is an ATP-dependent secretory drug efflux pump. In the intestine, as well as at specific
other epithelial and endothelial sites, P-glycoprotein expression is localised to the apical
membrane, consistent with secretory detoxifying and absorption limitation functions.
The primary function of Pgp is to clear the membrane lipid bilayer of lipophilic drugs.
Results from in vitro studies with human Caco-2 cells provide direct evidence for Pgp
limiting drug absorption. Limitation has non-linear dependence of absorption on
substrate (eg. vinblastine) concentration, increased absorption upon saturation of
secretion and increased absorption upon inhibition of Pgp function, with modulators such
as verapamil. The aim of this study was to investigate the effect of a known Pgp
inhibitor (verapamil) and grapefruit juice components (naringenin, quercetin and
bergamottin) on the transport of Rhodamine 123 across rat jejunum and to compare
these results with those obtained in similar studies done in Caco-2 cells and in rat
intestine (monodirectional). Verapamil, naringenin (442 µM, 662 µM and 884
µM), quercetin (73 µM, 183 µM and 292 µM) and bergamottin (12 µM, 30 µM and 48 µM)
were evaluated as modulators of rhodamine 123 transport across rat jejunum using
Sweetana-Grass diffusion cells. This study was done bidirectionally, with three cells
measuring transport in the apical to basolateral direction (AP / BL) and three cells
measuring transport in the basolateral to apical direction (BL / AP). The rate of transport
was expressed as the apparent permeability coefficient (Papp) and the extent of active
transport was expressed by calculating the ratio of BL/AP to AP/BL.
The BL-AP/AP-BL ratio calculated for Rhodamine 123 with no modulators added was 2.31. The
known modulator verapamil decreased the BL-AP/AP-BL ratio to 1.52. This was
statistically significant and inhibition of active transport was clearly demonstrated. All
modulators inhibited active transport. Only naringenin 884 µM, quercetin 183 µM and
bergamottin 30 µM did not show a statistically significant decrease in the BL-AP/AP-BL
ratio. All three components of grapefruit juice showed inhibition of active
transport and should have an effect on the bioavailability of the substrates of Pgp and
other active transporters. The results obtained in this study are similar to the results
found in Caco-2 cells, which suggests that Sweetana-Grass diffusion method can be
used for diffusion studies. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/599 |
| Date | January 2004 |
| Creators | Lamprecht, Christian Johannes |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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