Nitric oxide donors can enhance the intestinal transport and absorption of insulin and [Asu 1,7]-eel calcitonin in rats

The characteristics of three NO donors, 3-(2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine (NOC5), Nethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) as absorption enhancers for peptide drugs were examined in rats using a modified Ussing chamber method and an in situ closed loop method. Insulin and [Asu(1,7)]-eel calcitonin (ECT) were used as a model drug to investigate the effectiveness of the tested enhancers. The NO donors significantly increased the in vitro permeability of insulin across all intestinal membranes. In general, the absorption enhancement effects of these NO donors were greater in the colon than those in the jejunum and ileum. Of these NO donors, SNAP was the most effective enhancer. Their effects were concentration-dependent over the range of 0.01 to 0.1 mM. However, 0.1 mM NO donors had almost the same effects as those at 1 rnM concentration. The absorption-enhancing effects of the three NO donors were inhibited by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethy-limidazole-1-oxyl 3-oxide, sodium salt (carboxy-PTIO), an NO scavenger, suggesting that NO might be responsible for the efficacy of NO donors. In the in situ closed loop experiments, the three enhancers significantly improved the pharmacological availability % (PA%) of insulin in the small and large intestine. Similar results were also obtained when NO donors were added to ECT solution by an in situ closed loop method. These results suggest that NO donors possess excellent effectiveness for the use as absorption enhancers of peptide drugs and they are very effective at lower concentrations compared to the conventional enhancers. (c) 2005 Elsevier B.V. All rights reserved.