Comparison of RPMI 2650 cell layers and excised sheep nasal epithelial tissues in terms of nasal drug delivery and immunocytochemistry properties.

Nasal drug administration has been identified as a potential alternative to oral drug administration, especially for systemic delivery of large molecular weight compounds. Major advantages of nasal drug delivery include high vascularity and permeability of the epithelial membranes as well as circumvention of first-pass metabolism. RPMI 2650 cell layers (in vitro cell model) and excised sheep nasal mucosal tissues (ex vivo sheep model) were evaluated with regard to epithelial thickness, selected tight junction protein expression (i.e. claudin-1, F-actin chains, zonula occludin-1), extent of p-glycoprotein (P-gp) related efflux of a model compound (Rhodamine-123, R123) and paracellular permeation of a large molecular weight model compound (FITC-dextran 4400, FD4). The cell model grown under liquid cover conditions (LCC) was thinner (24 ± 4 µm) than the epithelial layer of the sheep model (53 ± 4 µm), whereas the thickness of cell model grown under air liquid interface (ALI) conditions (53 ± 8 µm) compared well with that of the sheep model. Although the location and distribution of tight junction proteins and F-actin differed to some extent between the cell model grown under ALI conditions and the sheep model, the extent of paracellular permeation of FD4 was similar (Papp = 0.48 × 10-6 cm.s-1 and 0.46 × 10-6 cm.s-1, respectively). Furthermore, the bi-directional permeation of R123 yielded the same efflux ratio (ER = 2.33) in both models. The permeation results from this exploratory study indicated similarity in terms of compound permeation between the RPMI 2650 nasal epithelial cell line and the excised sheep nasal epithelial tissue model.

Physicochemical Stability of Enriched Phenolic Fractions of Cyclopia genistoides and ex vivo Bi-directional Permeability of Major Xanthones and Benzophenones.

Fractions of an ultrafiltered Cyclopia genistoides extract, respectively enriched in xanthones and benzophenones, were previously shown to inhibit mammalian α-glucosidase in vitro. The present study investigated ex vivo intestinal transport of these fractions, using excised porcine jejunal tissue, to determine whether the gut could be a predominant in vivo site of action. The major bioactive compounds, the xanthones (mangiferin, isomangiferin) and benzophenones (3-ß-D-glucopyranosyliriflophenone, 3-ß-D-glucopyranosyl-4-O-ß-D-glucopyranosyliriflophenone) exhibited poor permeation in the absorptive direction with a relatively high efflux ratio (efflux ratio > 1). The efflux ratio of 3-ß-D-glucopyranosyl-4-O-ß-D-glucopyranosyliriflophenone (3.05) was similar to rhodamine 123 (2.99), a known substrate of intestinal P-glycoprotein 1 efflux transporters. Low epithelial membrane transport rates, coupled with efflux mechanisms, would effectively concentrate these bioactive compounds at the target site (gut lumen). Storage stability testing and moisture sorption assays of the xanthone-enriched fraction, benzophenone-enriched fraction, and ultrafiltered Cyclopia genistoides extract were performed to determine their susceptibility to physical and chemical degradation during storage. Hygroscopicity of the powders, indicated by moisture uptake, decreased in the order: benzophenone-enriched fraction (22.7%) > ultrafiltered Cyclopia genistoides extract (14.0%) > xanthone-enriched fraction (10.7%). 3-ß-D-Glucopyranosylmaclurin, a minor benzophenone, was the least stable of the compounds, degrading faster in the benzophenone-enriched fraction than in ultrafiltered Cyclopia genistoides extract, suggesting that the ultrafiltered extract matrix may provide a degree of protection against chemical degradation. Compound degradation during 12 wk of storage at 40 °C in moisture-impermeable containers was best explained by first order reaction kinetics.

Capsaicin and Piperine as Functional Excipients for Improved Drug Delivery across Nasal Epithelial Models.

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.

Beneficial Pharmacokinetic Drug Interactions: A Tool to Improve the Bioavailability of Poorly Permeable Drugs.

Simultaneous oral intake of herbs, supplements, foods and drugs with other drug(s) may result in pharmacokinetic or pharmacodynamic interactions with the latter. Although these interactions are often associated with unwanted effects such as adverse events or inefficacy, they can also produce effects that are potentially beneficial to the patient. Beneficial pharmacokinetic interactions include the improvement of the bioavailability of a drug (i.e., by enhancing absorption and/or inhibiting metabolism) or prolongation of a drug's plasma level within its therapeutic window (i.e., by decreasing excretion), whereas beneficial pharmacodynamic interactions include additive or synergistic effects. Mechanisms by which pharmacokinetic interactions can cause beneficial effects include enhancement of membrane permeation (e.g., structural changes in the epithelial cell membranes or opening of tight junctions), modulation of carrier proteins (e.g., inhibition of efflux transporters and stimulation of uptake transporters) and inhibition of metabolic enzymes. In the current review, selected pharmacokinetic interactions between drugs and various compounds from different sources including food, herb, dietary supplements and selected drugs are discussed. These interactions may be exploited in the future to the benefit of the patient, for example, by delivering drugs that are poorly bioavailable in therapeutic levels via alternative routes of administration than parenteral injection.

Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues.

Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp) related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123) were conducted in the absence (control group) and presence (experimental groups) of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M) increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate) changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies.