Absorption Of Fluorescein Isothiocyanate Dextrans Research Articles

Spermine with Sodium Taurocholate Enhances Pulmonary Absorption of Macromolecules in Rats.

The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α,Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration.

Nonlinear Intestinal Absorption of Fluorescein Isothiocyanate Dextran 4, 000 Caused by Absorptive and Secretory Transporting System

The mechanism of the nonlinear concentration dependence of the intestinal absorption of fluorescein isothiocyanate dextran 4,000 (FD-4) was studied using in situ rat intestinal loops and the in vitro Ussing-type chamber method. The intestinal absorption rate constant of FD-4, as evaluated by the intestinal loop method, increased significantly in a nonlinear fashion as the FD-4 concentration increased up to 0.2 mM and tended to decrease at concentrations higher than 0.2 mM. The mucosal-to-serosal permeation of FD-4 across rat ileal sheets, as evaluated by the in vitro Ussing-type chamber method, also increased in a nonlinear fashion in the low concentration range (0.01 - 0.02 mM), before decreasing as the concentration increased further, whereas serosal-to-mucosal permeation decreased in a concentration-dependent manner. In addition, mucosal-to-serosal flux and serosal-to-mucosal flux were increased and reduced in the presence of the metabolic inhibitor 2, 4-dinitrophenol, respectively. These results suggest that FD-4 is predominantly secreted into the intestinal lumen by an efflux transport system.

Characterization of the influence of nitric oxide donors on intestinal absorption of macromolecules

To characterize the influence of nitric oxide (NO) donors on the intestinal absorption of macromolecules, the relationship between the release rate of NO from NO donors and their absorption-enhancing effects and the effects of several scavengers and generators on the absorption-enhancing effects of NO donor were investigated. The t 1/2 values of the NO release rate from 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-1-propanamine (NOC5), 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)- N-methyl-1-propanamine (NOC7) and N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) are 25, 5 and 100 min, respectively. The absorption-enhancing effects of NO donors on the absorption of fluorescein isothiocyanate dextrans with an average molecular weight of 4400 (FD-4) are NOC5 > NOC7 > NOC12 in the colon. The lowest enhancing effect of NOC12 may be due to the slow rate of NO release. The enhancing effect of NOC7 rapidly disappeared compared with the effect of NOC5. The results raise the possibility that the difference between NOC5 and NOC7 on enhancing effect is related to the t 1/2 of the NO release. The NOC7-induced enhancing effect was prevented by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide sodium salt (C-PTIO), an NO scavenger; tiron, an O 2 − scavenger; mannitol, an OH scavenger, and deferoxamine, peroxynitrate scavenger. Pyrogallol, an O 2 − generator, potentiated the NOC7-induced enhancing effect. These results support a role for peroxynitrate, and possibly OH , in the NO donor-induced intestinal enhancing effect.

Improvement of Intestinal Absorption of Macromolecules by Nitric Oxide Donor

Nitric oxide (NO) is one of the most versatile mediators in mammalian biology. In the present study, we investigated the absorption‐enhancing effects of an NO donor, 3‐(2‐hydroxy‐1‐methylethyl‐2‐nitrosohydrazino)‐N‐methyl‐1‐propanamine (NOC7), on drugs that are poorly absorbed from the gastrointestinal tract. NOC7 significantly increased the jejunal absorption of fluorescein isothiocyanate dextrans (FDs) of different average molecular weights (4000–20,000). This enhancing effect decreased as the FD molecular weight increased. Another NO donor, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP), also increased the absorption of FD‐4 from the jejunum. The absorption enhancement effect of NOC7 significantly decreased after coadministration with an NO scavenger, 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazole‐1‐oxyl‐3‐oxide, sodium salt. Furthermore, the enhancement effect of NOC7 was reversed shortly after cessation of the enhancer treatment. Little damage by NOC7 to the intestinal mucosa was observed in terms of release of lactose dehydrogenase and protein from the intestinal mucosa. NOC7 also increased the absorption of FD‐4 by the colon and rectum. The findings suggest that an NO donor can improve the absorption of macromolecules from all regions of the rat intestine with very little mucosal damage and that an NO donor can act as a potent absorption enhancer. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1296–1304, 2000

Effect of absorption enhancers on pulmonary absorption of fluorescein isothiocyanate dextrans with various molecular weights

The effects of absorption enhancers on the pulmonary absorption of fluorescein isothiocyanate-labelled dextrans (FDs) with different average molecular weights (4000–150000) were examined by means of an in situ absorption method. Absorption enhancers used in this study were linoleic acid-surfactant mixed micelles (MM), N- lauryl-β- d -maltopyranoside (LM), diethyl maleate (DEM) and Na 2 EDTA. In the absence of absorption enhancers, the plasma concentration and percent absorption of FDs after intrapulmonary administration decreased with increase in their molecular weight. Of the absorption enhancers, MM and LM appeared to be more effective at enhancing the pulmonary absorption of FD with an approximate molecular weight of 40000 than DEM and Na 2 EDTA. MM showed the strongest enhancing effect on FD with an approximate molecular weight of 40000 while maximal effect of LM was observed in pulmonary absorption of the FD with an approximate molecular weight of 70000. These results suggest that lung may afford a favorable route for systemic delivery of macromolecules and absorption enhancers such as MM and LM may increase their pulmonary absorption.