Intestinal metabolism and absorption of cholecystokinin analogs in rats

Biochemical and Biophysical Research Communications
Sheng-Fang SuHye J Lee

Abstract

Intestinal metabolism and poor permeability were known to be major barriers for oral absorption of large peptide drugs. Dimensionless wall permeability values of C-terminal octa- and tetra-peptides cholecystokinin analogs (CCK8 and CCK4) were estimated and found out to be greater than 1, suggesting no permeability-limited absorption for CCK analogs. Thus, a strategy employing enzyme inhibitors and a specific delivery site to improve the absorption was developed and tested with CCK8, followed by identification of metabolites of the analogs and their participating enzymes in rabbit brush-border membrane vesicles. Thiorphan and amastatin, a specific enzyme inhibitor for enkephalinase and aminopeptidase, respectively, in pH 4 buffer solution were coadministered with CCK8 to the ileum in fistulated rats. The absolute bioavailability (F) of CCK8 was 5.4% and increased to 19% in the presence of the enzyme inhibitors, while the F values following oral administration were close to zero. These results indicate that peptide oral delivery is possible.

Citations

Apr 16, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Pan-Yue DengSaobo Lei
Oct 9, 2007·Journal of Pharmaceutical Sciences·Rajesh SinghJames W Lillard
Nov 16, 2002·Archives of Pharmacal Research·Hye J Lee
Dec 1, 2006·Nutrition Research Reviews·P GuilloteauR Zabielski

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