Effects of Renal Impairment on the Disposition of Orally Administered Enalapril, Benazepril, and Their Active Metabolites

Abstract

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 impairment. Ten dogs were randomly assigned to 2 groups of 5 animals in a 2-period crossover design for angiotensin-converting enzyme inhibitor administration. Renal failure was surgically induced by right nephrectomy and electrocoagulation of the remaining kidney. Renal mass reduction induced a significant decrease (P Ͻ .001) in glomerular filtration rate (GFR) (1.7 Ϯ 0.3 versus 3.3 Ϯ 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 Ϯ 14.7 to 42.4 Ϯ 20.9 g·minute/mL (P Ͻ .01). Mean peak plasma concentration (C max ) was increased in the impaired dogs (59.1 Ϯ 23.3 versus 43.9 Ϯ 32.9 ng/mL), but this variation was not significant (P Ͼ .05). Renal failure had no significant effect on AUC for benazeprilat (13.8 Ϯ 9.8 versus 14.9 Ϯ 5.0 g·minute/mL) (P Ͼ .05), but C max decreased significantly (from 55.0 Ϯ 26.4 to 31.9 Ϯ 17.7 ng/mL) (P Ͻ .05). Multiple regression analysis showed that both GFR and AUC for enalapril were highly significant variables that explained the variation in AUC for enalaprilat (R 2 ϭ .86, P Ͻ .001) but not for benazeprilat (R 2 ϭ .12, P Ͼ .05). The results of this study indicate that exposure to enalaprilat, but not to benazeprilat, is increased in dogs with subclinical renal impairment.

Effect of Benazepril on Survival and Cardiac Events in Dogs with Asymptomatic Mitral Valve Disease: A Retrospective Study of 141 Cases

“…In the BENCH study, the long‐term tolerability of BNZ in dogs with ISACHC class II and III CHF was also demonstrated, without any significant deleterious effects of BNZ on serum potassium concentration or renal or hepatic function 3,4 . Moreover, in contrast to humans, BNZ pharmacokinetics and pharmacodynamics are not altered in dogs with renal impairment 23,24 . The good tolerance of BNZ was also recently demonstrated in asymptomatic dogs affected by mild MVD (ISACHC class 1a) in a prospective, randomized, and blinded study performed by our group 12 .…”

Pharmacologic management of myxomatous mitral valve disease in dogs

“…These agents have plasma half-lives of approximately 8e16 h. 83 Some (benazepril and enalapril) do differ slightly with regards to tissue penetration and route of extretion. 96 Because benazepril is excreted both renally and hepatically, there is little or no increase in plasma benazeprilat (active metabolite) in dogs with chronic kidney disease/failure, as compared to enalaprilat, concentrations which are elevated in the face of renal failure. 96, 97 The clinical importance of this has not been established.…”

“…96 Because benazepril is excreted both renally and hepatically, there is little or no increase in plasma benazeprilat (active metabolite) in dogs with chronic kidney disease/failure, as compared to enalaprilat, concentrations which are elevated in the face of renal failure. 96, 97 The clinical importance of this has not been established. A second potentially important difference is that benazepril has better tissue ACE inhibitory capability than most ACE-I, including enalapril.…”

Management of Proteinuria in Dogs and Cats with Chronic Kidney Disease

“…There is no scientific basis to support that one ACEi has superior pharmacodynamic action. Benazepril and its active metabolite, benazeprilat, are largely eliminated by the biliary route with a smaller fraction being excreted in the urine; impaired renal function does not affect the clearance of this drug in dogs (Lefebvre et al, 1999). On the other hand, enalapril and its active metabolite, enalaprilat, are primarily eliminated by the kidney.…”