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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 active moiety of benazepril, and of enalaprilat, the active moiety of enalapril, two angiotensin-converting enzyme (ACE) inhibitors (ACEI), having different routes of elimination in dog was investigated during a mild renal insufficiency obtained by a nephrectomy-electrocoagulation method reducing glomerular filtration rate by approximately 50%. Plasma concentrations of the active moieties were analyzed with a physiologically based model taking into account the binding to ACE (high affinity, low capacity). An influence of renal insufficiency on enalapril disposition was shown with an increase in its plasma concentration, which was correlated to the reduction of the glomerular filtration rate. No such effect was evidenced for benazepril. With the physiologically 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 significant effect either on the apparent volume of distribution of each drug or on the binding parameters [i.e., maximal binding capacity (B(max)) and affinity (K(d))]. Enalaprilat and benazeprilat inhibitory action on ACE also was evaluated ex vivo. Similar patterns of inhibition were observed for both drugs. Renal injury had no significant influence on the overall effect of benazeprilat, whereas the inhibition effect of enalaprilat was significantly increased. It was concluded that renal insufficiency may have effects on the ACEI disposition but that the measurable active moiety plasma concentration is not the most appropriate endpoint to describe and interpret the consequence of a renal injury on ACEI.