| dc.description.abstract | Although the oral route is the most preferred and convenient route of drug administration when considering the patient, certain drugs (e.g. protein and peptide drugs) are mostly administrated by means of injections. This invasive route of administration causes poor patient compliance due to drawbacks such as pain, discomfort, possibility of infections and lipohypertrophy. Hurdles related to oral administration of protein and peptide drugs include pre-systemic enzymatic degradation as well as poor penetration of the intestinal mucosa, leading to ineffective absorption in the intestinal tissue. Poor membrane permeation can be overcome by the simultaneous administration of the drug molecule with an absorption enhancer. Previous studies have proven that absorption enhancers of natural origin, e.g. Aloe vera leaf materials, bile salts, naringin, turmeric and peppermint oil can improve the absorption of drug molecules as shown in different intestinal epithelial transport models. During this study, pepper extract compounds (i.e. piperine and capsaicin) were investigated as potential intestinal drug absorption enhancers. Ex vivo transport studies were conducted across excised pig jejunum tissue mounted in a Sweetana-Grass diffusion apparatus. The effect of the selected pepper extract compounds on rhodamine-123 (RH-123, 5 μM) and fluorescein isothiocyanate (FITC)-dextran (FD-4, 100 μg/ml) was investigated. Bi-directional transport studies were conducted on RH-123, a known P-glycoprotein (P-gp) efflux transporter substrate, to determine if piperine and capsaicin have the ability to inhibit P-gp efflux. Transport studies in the absorptive direction were conducted on FD-4, a macromolecular model drug, to determine if piperine and capsaicin have the ability to open tight junctions and thereby cause enhanced paracellular transport. The transport studies were conducted over a time period of 2 h, while taking 200 μL samples every 20 min from the acceptor chamber. These samples were then analysed by means of a validated fluorescence analytical method on the Spectramax Paradigm® plate reader. The trans-epithelial electrical resistance (TEER) of the mounted excised pig intestinal tissue was measured every 20 min to determine membrane integrity and also as an indication of tight junction modulation. For each model compound, a transport study was conducted without any absorption enhancing agent, which served as the control groups. The permeability coefficient (Papp) values of the transport experiments were calculated from the transport curves. Piperine and capsaicin improved the absorption of RH-123 in a concentration dependant manner in the apical-to-basolateral (AP-BL) direction across the intestinal tissue when compared with the control group. The Papp values of RH-123 in the AP-BL direction increased from 1.54×10-7 cm/s (RH-123 alone) to 1.65×10-7 cm/s, 1.56×10-7 cm/s and 2.859×10-7 cm/s in the presence of piperine in 50 μM, 100 μM and 200 μM, respectively. Furthermore, the Papp values increased from 1.54×10-7 cm/s (RH-123 alone) to 4.09×10-7 cm/s, 6.11×10-7 cm/s and 8.15×10-7 cm/s in the presence of capsaicin in 50 μM, 100 μM and 200 μM, respectively. In accordance with this enhanced absorptive transport result, RH-123 transport was decreased in the basolateral-to-apical (BL-AP) direction in a concentration dependant manner when compared with the control group. The Papp value of RH-123 in the BL-AP direction decreased from 5.28×10-7 cm/s (RH-123 alone) to 4.17×10-7 cm/s, 2.71×10-7 cm/s and 2.49×10-7 cm/s in the presence of piperine in 50 μM, 100 μM and 200 μM, respectively. Furthermore, the Papp value decreased from 5.28×10-7 cm/s (RH-123 alone) to 4.2×10-7 cm/s, 2.44×10-7 cm/s and 2.68×10-7 cm/s in the presence of capsaicin in 50 μM, 100 μM and 200 μM, respectively. These results indicated that piperine and capsaicin have the ability to inhibit P-gp efflux and thereby enhance the absorptive transport of efflux transporter substrates. During the transport studies with FD-4 in the presence of piperine, the absorption of FD-4 increased as the piperine concentration increased, while the TEER values decreased. The Papp values of FD-4 increased from 1.76×10-7cm/s (FD-4 alone) to 3.6×10-7 cm/s, 4.06×10-7cm/s and 4.39×10-7cm/s in the presence of piperine in 50 μM, 100 μM and 200 μM, respectively. These results indicate that piperine has the ability to open tight junctions and thereby improve paracellular transport across the excised intestinal tissue. During transport studies with FD-4 in the presence of capsaicin, the absorption of FD-4 did not increase and the TEER values remained stable. Capsaicin therefore did not show the ability to modulate tight junctions to allow enhanced paracellular transport across the intestinal tissues. Although very promising drug absorption enhancing results were obtained for piperine and capsaicin with the ex vivo transport studies, in vivo studies are necessary to determine if these absorption enhancers have the ability to improve drug absorption in a clinically significant way. | en_US |
