ABSORPTION OF ACE-INHIBITORS FROM SMALL-INTESTINE AND COLON

The intestinal absorption of two ACE inhibitors was studied to determi ne the potential for colonic delivery of small peptides. In addition, studies were also performed to assess intestinal tissue uptake and eva luate a canine intestinal-access-port model as techniques for screenin g absorption. To evaluate the impact of differences in the contributio ns of passive permeation and carrier-mediated peptide transport on in vitro uptake and in vivo absorption, an esterified prodrug, benazepril , and a free diacid non-prodrug, CGS 16617, were selected for study. P otential colonic absorption enhancement utilizing coadministration of Intralipid was also investigated. Studies in rat everted intestinal ri ngs verified that jejunal benazepril uptake included a carrier-mediate d component while that of the diacid did not. Uptake of both drugs was purely passive in colonic rings. Equilibrium uptake and uptake rate o f the more lipophilic prodrug was 2-fold greater than the diacid. Bena zepril and CGS 16617 jejunal uptake rate at 0.01 mM was 3.5 and 2.5 ti mes higher, respectively, than from colonic rings. Following jejunal a dministration in dogs, maximum benazepril plasma levels (C-max) and ar ea under the plasma level versus time curve (AUC) were 5.5 and 3.0 tim es higher, respectively, than following colonic administration. Maximu m benazepril plasma levels following colonic administration in dogs wa s 2-fold greater than for CGS 16617, consistent with in vitro results. Colonic coadministration of the poorly-absorbed CGS 16617 with 2 mt o f Intralipid (within dietary range for fecal fat content) enhanced C-m ax and AUC 2.5- and 3.5-fold, respectively, in the dog and AUC 1.5-fol d in the rat. Morphological and biochemical studies showed that Intral ipid did not damage rat jejunal or colonic epithelium in situ.