Libenzapril

The intestinal absorption of two ACE inhibitors was studied to determine the potential for colonic delivery of small peptides. In addition, studies were also performed to assess intestinal tissue uptake and evaluate a canine intestinal-access-port model as techniques for screening absorption. To evaluate the impact of differences in the contributions 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. Potential colonic absorption enhancement utilizing coadministration of Intralipid was also investigated. Studies in rat everted intestinal rings verified that jejunal benazepril uptake included a carrier-mediated component while that of the diacid did not. Uptake of both drugs was purely passive in colonic rings. Equilibrium uptake and uptake rate of the more lipophilic prodrug was 2-fold greater than the diacid. Benazepril and CGS 16617 jejunal uptake rate at 0.01 mM was 3.5 and 2.5 times higher, respectively, than from colonic rings. Following jejunal administration in dogs, maximum benazepril plasma levels (Cmax) and area under the plasma level versus time curve (AUC) were 5.5 and 3.0 times higher, respectively, than following colonic administration. Maximum benazepril plasma levels following colonic administration in dogs was 2-fold greater than for CGS 16617, consistent with in vitro results. Colonic coadministration of the poorly-absorbed CGS 16617 with 2 mL of Intralipid (within dietary range for fecal fat content) enhanced Cmax and AUC 2.5- and 3.5-fold, respectively, in the dog and AUC 1.5-fold in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of these experiments was to determine whether, in carotid arteries obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) a correlation exists between access of the angiotensin-converting enzyme (ACE) inhibitor, 3-[(5-amino-1-carboxy-1S-pentyl)amino]2,3,4,5-tetrahydro-2-oxo-3S- 1H-benzazepena-1-acetic acid (CGS 16617), to tissue sites and the corresponding responsiveness of these tissues to the contractile effect of angiotensin I (ANG I). In carotid arteries isolated from SHR and WKY, the magnitude of [14C]CGS 16617 uptake was slightly greater than the [14C]sucrose uptake (the extracellular space), and the percentages of [14C]CGS 16617 and [14C]sucrose in fast and slow desaturation components were similar. Addition of high concentrations of nonradioactive CGS 16617 (10(-5)M during uptakes or washouts of [14C]CGS 16617 did not change uptake amounts or efflux rates. The dose-response curves of contractions obtained with ANG I or ANG II as well as the dose-dependent inhibition of ANG I-induced responses in the presence of CGS 16617 were similar for carotids taken from both WKY and SHR. Responses to ANG I were restored as early as 5 min after incubation solutions containing inhibitory concentrations of CGS 16617 were removed. Similarly, normal responsiveness to the contractile effects of ANG I were observed with carotid arteries removed from SHR with decreased blood pressure and plasma ACE activity after 5 weeks exposure to CGS 16617. In contrast, however, responses to norepinephrine were decreased in carotid arteries obtained from CGS 16617-treated SHR.(ABSTRACT TRUNCATED AT 250 WORDS)