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.

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.