Effects of renal impairment on the disposition of orally administered enalapril, benazepril, and their active metabolites

The pharmacokinetics of benazepril, enalapril, and their active metabolites (benazeprilat and enalaprilat) were compared after a single administration of each product by the oral route at the recommended dosage (0.5 mg/kg for both drugs) in the dog before and after moderate experimental renal impair ment. Ten dogs were randomly assigned to 2 groups of 5 animals in a 2-perio d crossover design for angiotensin-converting enzyme inhibitor administrati on. Renal failure was surgically induced by right nephrectomy and electroco agulation of the remaining kidney. Renal mass reduction induced a significa nt decrease (P < .001) in glomerular filtration rate (GFR) (1.7 +/- 0.3 ver sus 3.3 +/- 0.7 mL/kg/minute). No significant differences before and after surgery were observed for enalapril and benazepril kinetics. The area under the curve (AUC) for enalaprilat increased after surgery from 23.6 +/- 14.7 to 42.4 +/- 20.9 mu g minute/mL (P < .01). Mean peak plasma concentration (C-max) was increased in the impaired dogs (59.1 +/- 23.3 versus 43.9 +/- 3 2.9 ng/mL), but this variation was not significant (P >. 05). Renal failure had no significant effect on AUC for benazeprilat (13.8 +/- 9.8 versus 14. 9 +/- 5.0 mu g.minute/ml) (P > .05), but C-max decreased significantly (fro m 55.0 +/- 26.4 to 31.9 +/- 17.7 ng/mL) (P < .05). Multiple regression anal ysis showed that both GFR and AUC for enalapril were highly significant var iables that explained the variation in AUC for enalaprilat (R-2 = .86, P < .001) but not for benazeprilat (R-2 = .12, P > .05). The results of this st udy indicate that exposure to enalaprilat, but not to benazeprilat, is incr eased in dogs with subclinical renal impairment.