Many orally administered drugs must overcome several barriers before reaching their target site. The first major obstacle to cross is the intestinal epithelium. Although lipophilic compounds may readily diffuse across the apical plasma membrane, their subsequent passage across the basolateral membrane and into blood is by no means guaranteed. Efflux proteins located at the apical membrane, which include P-glycoprotein (P-gp, MDR1) and Multidrug Resistance-associated Protein (MRP2), may drive compounds from inside the cell back into the intestinal lumen, preventing their absorption into the blood. Intestinal P-gp is localised to the villus tip enterocytes, i.e. the main site of absorption for orally administered compounds and in close proximity to the lumen. P-gp is therefore ideally positioned to limit the absorption of compounds by driving efflux back into the lumen. Drugs may also be modified by intracellular phase I and phase II metabolizing enzymes. This process may not only render the drug ineffective, but it may also produce metabolites that are themselves substrates for P-gp and/or MRP2. Drugs that reach the blood are then passed to the liver, where they are subjected to further metabolism and biliary excretion, often by a similar system of ATP binding cassette (ABC) transporters and enzymes to that present in the intestine. Thus a synergistic relationship exists between intestinal drug metabolizing enzymes and apical efflux transporters, a partnership that proves to be a critical determinant of oral bioavailability. Aim: The aim of this study was to investigate the effect of selected methoxy flavonoids (3-methoxyflavone, 5-methoxyflavone, 6-methoxyflavone and 7- methoxyflavone) on the mean ratio of Rhodamine123 (Rho 123) transport across rat intestine (jejunum) and to investigate structure activity relationships (SAR) of the selected flavonoids with reference to inhibition of P-gp. Methods: 3-Methoxyflavone, 5- methoxyflavone, 6-methoxyflavone and 7-methoxyflavone were evaluated at a concentration of 10μM and 20μM as modulators of Rho 123 transport across rat jejunum. The Sweetana-Grass diffusion cells were used to determine the transport of Rho 123. Each modulator was studied bidirectionally with two cells measuring transport in the apical to basolateral direction (AP/BL) and two cells measuring transport in the basolateral to apical direction (BUAP). 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 BUAP to AP/BL. Each modulators Papp ratio was then compared with that of the control. Results: 3-Methoxyflavone decreased the Papp ratio from 3.34 (control) to 1.66 (10μM) and 1.33 (20μM) and showed statistical significant differences. 7-Methoxyflavone decreased the Papp ratio to 1.94 (10μM) and 1.55 (20μM) but only showed a statistical significant difference at 10μM. 5- Methoxyflavone decreased the Papp ratio to 2.41 (10μM) and 1.71 (20μM) and 6- methoxyflavone decreased the Papp to 3.03 (10μM) and 2.49 (20μM). Both 5- and 6- methoxyflavone showed no statistical significant differences from the control. The structure activity relationships with reference to P-gp inhibition clearly indicated that the C3 and C7 positioning of the methoxy-group on the A ring played a major role in the inhibition of Rho 123 transport. Conclusion: All the selected modulators showed inhibition of Rho 123 transport across the jejunum. This should affect the bioavailability of the substrates of P-gp and other active transporters. In summary, this study describe the inhibitory interaction of selected flavonoids with P-gp. Structure activity relationships were identified describing the inhibitory potency of the flavonoids based on methoxy groups positioning. The inhibitory potency results were 3-methoxyflavone > 7- methoxyflavone > 5-methoxyflavone> 6-methoxyflavone / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

Background: Multidrug resistance (MDR) is resistance of cancer cells to multiple classes of chemotherapeutic drugs that can be structurally unrelated. MDR involves altered membrane transport that results in a lower cell concentration of cytotoxic drugs which plays an important role during cancer treatment. P-glycoprotein (Pgp) is localised at the apical surface of epithelial cell in the intestine and it functions as a biological barrier by extruding toxic substances and xenobiotics out of cells (Lin, 2003:54). The ATP-binding-cassette superfamily is a rapidly growing group of membrane transport proteins and are involved in diverse physiological processes which include antigen presentation, drug efflux from cancer cells, bacterial nutrient uptake and cystic fibrosis (Germann, 1996:928; Kerr, 2002:47). A number of drugs have been identified which are able to reverse the effects of Pgp, multidrug resistance protein (MRPI) and their associated proteins on multidrug resistance. The first MDR modulators discovered and studied during clinical trials were associated with definite pharmacological actions, but the doses required to overcome MDR were associated with the occurrence of unacceptable side effects. As a consequence, more attention has been given to the development of modulators with proper potency, selectivity and pharmacokinetic characteristics that it can be used at a lower dose. Several novel MDR reversing agents (also known as chemosensitisers) are currently undergoing clinical evaluation for the treatment of resistant tumours (Teodori et al., 2002:385). Aim: The aim of this study was to investigate the effect of selected flavonoids (morin, galangin, kaempferol and quercetin) at two different concentrations (10 μM and 20 μM) on the transport of a known Pgp substrate, Rhodamine 123 (Rho 123) across rat intestine (jejunum) and to investigate structure activity relationships (SAR) of the selected flavonoids with reference to the inhibition of Pgp. Methods: Morin, galangin, kaempferol and quercetin were evaluated as potential modulators of Rho 123 transport, each at a concentration of 10 μM and 20 μM across rat jejunum using Sweetana-Grass diffusion cells. This study was done bidirectionally, with two cells measuring transport in the apical to basolateral direction (AP-BL) and two cells measuring transport in the basolateral to apical direction (BL-AP). The rate of transport was expressed as the apparent permeability coefficient (Pap,) and the extent of active transport was expressed by calculating the ratio of BL-AP to AP-BL. Results: The BL-AP to AP-BL ratio calculated for Rho 123 with no modulators added was 3.29. Morin decreased the BL-AP to AP-BL ratio to 1.88 at a concentration of 10 μM and to 1.49 at a concentration of 20 μM. Galangin decreased the BL-AP to AP-BL ratio to 1.60 at a concentration of 20 μM. These two flavonoids showed statistically significant results and inhibition of active transport were clearly demonstrated. However, the other flavonoids inhibited active transport of Rho 123 but according to statistical analysis, the results were not significantly different. The two different concentrations (10 μM and 20 μM) indicated that galangin, kaempferol and quercetin showed practically significant differences according to the effect sizes. Morin, however, did not show any practically significant differences at the different concentrations. Regarding .the SAR, it was shown by Boumendjel and co-workers (2002:512) that the presence of a 5-hydroxyl group and a 3-hydroxyl group as well as the C2-C3 double bond are required for high potency binding to the nucleotide binding domain (NBD) of Pgp. All the flavonoids tested had the above-mentioned characteristics. Conclusion: All the selected flavonoids showed inhibition of active transport of Rho 123 and should have an effect on the bioavailability of the substrates of Pgp and other active transporters. This study described the inhibitory interaction of selected flavonoids on Pgp activity. Practical significant differences between the same modulator at different concentrations were also observed. Structure activity relationships were identified describing the inhibitory potency of the flavonoids based on hydroxyl group positioning / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.

Made available in DSpace on 2014-10-09T12:46:45Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:33Z (GMT). No. of bitstreams: 1 08366.pdf: 2503408 bytes, checksum: 7a96383a00a09101cb3350bf14e5b149 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:50:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:25Z (GMT). No. of bitstreams: 1 11107.pdf: 5050996 bytes, checksum: 5619119599cfe5e14f17122301eaafa7 (MD5) / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:52:20Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:00:49Z (GMT). No. of bitstreams: 0 / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:50:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:25Z (GMT). No. of bitstreams: 1 11107.pdf: 5050996 bytes, checksum: 5619119599cfe5e14f17122301eaafa7 (MD5) / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:46:45Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:33Z (GMT). No. of bitstreams: 1 08366.pdf: 2503408 bytes, checksum: 7a96383a00a09101cb3350bf14e5b149 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Made available in DSpace on 2014-10-09T12:52:20Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:00:49Z (GMT). No. of bitstreams: 0 / O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

No description available.

No description available.