Plasma Concentrations of an Angiotensin-Converting Enzyme Inhibitor, Benazepril, and Its Active Metabolite, Benazeprilat, after Repeated Administrations of Benazepril in Dogs with Experimental Kidney Impairment.

Abstract

ABSTRACT. In order to examine the safety of an angiotensin-converting enzyme (ACE) inhibitor in dogs with impaired renal excretion route, benazepril was administered orally, and plasma concentrations of benazeprilat, the active metabolite of benazepril, were determined in dogs with renal mass reduction (1/4th kidney) created by right-side nephrectomy and ligation of branches of the left renal arteries. Five dogs were administered benazepril orally at a given dose (0.5 mg/kg body weight) and 4 other dogs received 20 times that dose (10 mg/kg body weight) once daily for 15 consecutive days before (intact kidney period) and after (1/4th kidney period) creation of kidney impairment. Six control dogs received surgical treatment, but no drug. After creating a 1/4th kidney, plasma urea nitrogen and creatinine concentrations increased to approximately 30 mg/dl and 2.0 mg/dl, respectively, and renal plasma flow and glomerular filtration rate decreased to 37% and 30% of pre-treatment values, respectively. However, these parameters did not change significantly during the 1/4th kidney period both in the 0.5 mg/kg and 10 mg/kg groups. In the 0.5 mg/kg group, plasma benazeprilat concentrations increased to approximately 20 ng/ml to 340 ng/ml 2 hr after each administration, and there were no significant differences between the plasma benazeprilat concentrations during the intact and 1/4th kidney periods. In the 10 mg/kg group, plasma benazeprilat concentrations varied in the individual dog, but did not increase with the days of administration, and were not significantly different on each administration day between the intact and 1/4th kidney periods in either dose group. The AUCs(0-24) of plasma benazeprilat concentrations determined on the 15th administration day were not different between the intact and 1/4th kidney periods in dogs of either dose group. Plasma ACE activities decreased after drug administration in dogs of both groups. Benazepril seemed to have a high safety, and the adjustment of dosage regimen might not be needed in dogs with mild to moderate renal function impairment because the drug was excreted both from the kidneys and liver.-KEY WORDS: angiotensin-converting enzyme inhibitor, benazepril, canine, plasma concentration, renal impairment.

Development of Hypertension and Effects of Benazepril Hydrochloride in a Canine Remnant Kidney Model of Chronic Renal Failure

“…These findings indicate that systemic hypertension was experimentally induced by reducing the functioning nephrons, and suggest that the RAA system was involved in the development of nephron loss associated-hypertension in dogs. Kitagawa et al [21] performed 3/4 renal ablation in healthy dogs and, approximately 1 month later, found increases in BUN and Cr and decreases in renal plasma flow and glomerular filtration rate, while they found no significant changes in oscillometrically determined mean blood pressure. Brown et al [11] found increases in glomerular pressure 1 month after 3/4 renal ablation, but blood pressure was not increased.…”

“…Although we used benazepril at 2 mg/kg/day, twice the upper limit of the commonly-used dose, to ensure the drug's pharmacological effects, neither marked decrease in systemic blood pressure nor aggravation of renal function were observed. Kitagawa et al [21] administered benazepril to dogs with renal ablation for 15 days at 10 mg/ kg/day, 20-fold the upper limit of the commonly-used dose; however, blood pressure remained at the pre-ablation levels and no improvement was seen in BUN or Cr. Together with the fact that they found no increase in blood pressure in dogs with 3/4 renal ablation, their findings suggest that the RAA system was not activated.…”

“…The clearance of benazeprilat, the effective metabolite of benazepril, increased in dogs with experimentally induced renal failure, whereas clearance was decreased to 40 to 55% for the effective metabolite of enalapril [39]. Studies by Kitagawa et al [21] have shown that benazepril hydrochloride does not accumulate in animals with renal insufficiency, suggesting that benazepril is a safe medication for chronic renal failure in small animals. Our present study also shows that benazepril was associated with neither acute reduction of renal function nor hypotension, and blood pressure recovered to the pre-administration levels after discontinuation of benazepril, further underlining short-lived and reversible actions of benazepril.…”

Tratamento de insuficiência cardíaca com benazepril em cães com cardiomiopatia dilatada e endocardiose

“…O benazepril tem ação por 24 horas, podendo ser administrado uma vez ao dia (King et al, 1995). Ele é excretado tanto por via renal quanto hepática, não necessitando de ajuste na dose em pacientes com insuficiência renal (Kitagawa et al, 2000).…”

Effects of Benazepril Hydrochloride in Cats with Experimentally Induced or Spontaneously Occurring Chronic Renal Failure

“…Of the available ACE inhibitors, benazepril hydrochloride (BH) is different in that BH is excreted in both bile and urine [44]. Because of this property, BH does not accumulate in the body of animals with renal dysfunction [19], indicating its potential as a safe therapeutic means for CRF of small animals.In the present study, we examined therapeutic effects of BH on CRF and renal hypertension in cats. To this end, we experimentally induced CRF in cats by renal ablation, and examined the effects of BH on blood pressure and the activity of the RAA system.…”