Excellent Absorption Enhancing Characteristics of NO Donors for Improving the Intestinal Absorption of Poorly Absorbable Compound Compared with Conventional Absorption Enhancers

Abstract

The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.

Absorption-Enhancing Effect of Nitric Oxide on the Absorption of Hydrophobic Drugs in Rat Duodenum

“…It is notable that the absorption-enhancing effect of NO on the absorption of FD-4, a paracellular marker, has been reportedly observed in the entire intestinal region, with the greatest enhancement observed in the colon. 11,13 This discrepancy between the present and the previous results may be attributed to the differences in the mechanism of NO action between the transcellular and paracellular routes. Therefore, in subsequent experiments, we examined the effect of NOC7 on drug permeation in the duodenum by the transcellular route.…”

Intestinal absorption of S-nitrosothiols: Permeability and transport mechanisms

“…The amount of NOx species found inside the cells was higher for the GSNO treatment than for the SNAP treatment, with the NACNO treatment situated between each other. SNAP promotes drug intestinal absorption [41] by opening tight junctions without affecting barrier integrity. Indeed, SNAP increases insulin rectal absorption, transep ithelial transport of fluorescein sulfonic acid (low absorbable molecule) [41,42] and macromolecules absorption through the intestine by the reversible opening of tight junctions [41,43,44] and a thickening of ileal mucosal membrane [45].…”

Does pH of tyrode solution modify glucose and electrolyte jejunal absorption in rats?

“…Several factors can affect the intestinal absorption of glucose, electrolytes and water, such as nutritional deficiency [6] or absorption modulation by hormones [7] and peptides [8][9][10][11][12] via the autonomic nervous system. However, the different experimental models used in absorption studies have employed different physiological solutions for infusion, such as Ringer's solution [13], Krebs' solution [14], Tyrode solution [8][9][10][11]14,15] and phosphate buffer [16,17], with a broad range of variation in the pH of these solutions (pH 7 to pH 8).…”