COLONIC ABSORPTION AND BIOAVAILABILITY OF THE PENTAPEPTIDE METKEPHAMID IN THE RAT

The concept of delivering systemically active peptide drugs to the col on in order to improve their oral absorption requires reasonable pepti de permeability of the large intestinal wall and stability against the activity of the colonic microflora. In addition, the role of hepatic extraction needs to be addressed. In this study the absorption of the pentapeptide metkephamid following single pass perfusion of rat ascend ing colon was investigated by monitoring its disappearance from the la rge intestine and simultaneous appearance in the portal vein, the hepa tic vein and the aorta. In addition its stability against colonic micr oflora was tested in vitro using pig caecal contents. Metkephamid was absorbed from the large intestine and appeared in the blood circulatio n; peptide concentrations in the portal vein increased over-proportion ally with increasing perfusate concentrations (0.1 - 4.6 mmol/L) from 0.19 mu g/mL +/- 0.12 (SD, n=7) to 31.6 mu g/mL + 20.65 (SD, n=4), res pectively, and thus suggesting a saturable transport or metabolism. Co ncentrations in the hepatic vein were significantly lower than in the portal vein, hepatic extraction ratios were 0.35 +/- 0.14, 0.61 +/- 0. 18 and 0.62 +/- 0.28 (SD, n=4) for 0.1, 0.5 and 1.0 mM metkephamid per fusate concentrations, respectively. In the anaerobic colon metabolism model the degradation half-life of the peptide was 14.9 hours, thus, indicating relative stability in the bacterial environment of the colo n. The results of the present study encourage further investigations o n colonic delivery of peptide drugs.