Oral absorption of ACE inhibitors.

Abstract

In order to elucidate the mechanism and structural requirement for transport via the intestinal peptide carrier system, the transport characteristics of the angiotensin-converting enzyme inhibitor (ACE-I) enalapril, and three other new ACE-I's, quinapril, benazepril, and CGS 16617 were investigated using brush border membrane vesicles from the rabbit jejunum and an in situ single pass perfusion of rat jejunum, respectively. In addition, since captopril (an ACE-I) and cephradine (an oral antibiotic) have been shown to be absorbed by the same peptide transport pathway, the significance of the potential drug interaction between these two drugs was investigated in healthy subjects. In vitro analysis of ($\sp{14}$C) -enalapril uptake using a rapid filtration technique demonstrated trans stimulation by cephradine and cefadroxil and trans inhibition by lisinopril and enalapril. The results of trans stimulation of enalapril uptake by cephradine and cefadroxil further supports the suggestion that ACE inhibitors are transported in part by the peptide carrier across the transepithelial membrane. Enalaprilat acted as a competitive inhibitor of enalapril by binding at the substrate site without undergoing transport. Cephradine, enalaprilat, lisinopril and quinapril competitively inhibited the transport of enalapril in zero trans experiments with K$\sb{\rm i}$ values of 4.79 mM, 5.76 mM, 0.11 mM, and 0.89 mM, respectively. The prodrugs quinapril and benazepril were well absorbed with parallel saturable and passive mechanisms. In contrast, their respective active diacids, quinaprilat and benazeprilat were poorly absorbed. Both saturable absorption and competitive inhibition by peptide absorption inhibitors indicated that quinapril and benazepril are transported via the peptide pathway. The diacid CGS 16617 has a low permeability, and its transport mechanism could not be elucidated using this technique. The oral bioavailability of several of the prodrug ACE inhibitors may be limited by pre-absorptive gut metabolism and post-absorptive biliary excretion. The pharmacokinetics of captopril was determined in an open, randomized three-way crossover design. Nine healthy subjects were given either an oral dose of captopril (25 mg) or cephradine (500 mg) or their combination. Although the mean AUC and C$\sb{\rm max}$ were lower with a longer T$\sb{\rm max},$ following oral coadministration of captopril and cephradine, these differences in parameter estimates were not statistically significant.