New insights on effect of kidney insufficiency on disposition of angiotensin-converting enzyme inhibitors: Case of enalapril and benazepril in dogs

The influence of a renal injury on the disposition of benazeprilat, the act ive moiety of benazepril, and of enalaprilat, the active moiety of enalapri l, two angiotensin-converting enzyme (ACE) inhibitors (ACEI), having differ ent routes of elimination in dog was investigated during a mild renal insuf ficiency obtained by a nephrectomy-electrocoagulation method reducing glome rular filtration rate by similar to 50%. Plasma concentrations of the activ e moieties were analyzed with a physiologically based model taking into acc ount the binding to ACE (high affinity, low capacity). An influence of rena l insufficiency on enalapril disposition was shown with an increase in its plasma concentration, which was correlated to the reduction of the glomerul ar filtration rate. No such effect was evidenced for benazepril. With the p hysiologically based model analysis, it was shown that renal impairment led to an increase of the apparent benazeprilat clearance (260%), whereas that of enalaprilat was reduced to 40 to 55%. Renal insufficiency had no signif icant effect either on the apparent volume of distribution of each drug or on the binding parameters [i.e., maximal binding capacity (B-max) and affin ity (K-d)]. Enalaprilat and benazeprilat inhibitory action on ACE also was evaluated ex vivo. Similar patterns of inhibition were observed for both dr ugs. Renal injury had no significant influence on the overall effect of ben azeprilat, whereas the inhibition effect of enalaprilat was significantly i ncreased. It was concluded that renal insufficiency may have effects on the ACEI disposition but that the measurable active moiety plasma concentratio n is not the most appropriate endpoint to describe and interpret the conseq uence of a renal injury on ACEI.