Azetireiin, a new thyrotropin-releasing hormone (TRH)analogue, has much more potent and longer-lasting activity on the central nervous system than TRH. It is known, however, that the oral bioavailability of azetirelin is poor and less than 2% in rats and humans. This is mainly attributed to the low intestinal permeability due to the lack of lipophilicity. We have studied the effect of various absorption enhancers on the intestinal absorption of azetirelin by means of in vitro Ussing chamber and in situ closed loop experiments. Enhancers such as Na2-EDTA, sodium glycocholatc(Na-GC), citric acid, and laurylmaltoside(LM) were used in the study. The action of these enhancers was more predominant in the large intestine than in the small intestine. LM was most effective among the enhancers studied. The enhancing activity of LM was concentration dependent and the effect of 1mM LM was still more extensive than that of 10mM of other enhancers. The release amount of membrane protein and phospholipid in the presence of these enhancers was also examined to evaluate the tissue damage. The results indicated that 1mM LM was less harmful to the large intestinal mucosa than 10mM Na2-EDTA or Na-GC. From these results, we conclude that LM is practically safe and effective absorption enhancer for improving the large intestinal absorption of azetirelin.
